Process for preparing 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines

ABSTRACT

A method of preparing intermediates for making 1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amines is disclosed.

[0001] This application is a continuation-in-part of commonly assignedcopending application U.S. Ser. No. 07/838,475, filed Feb. 19, 1992, nowabandoned, which is a continuation-in-part of commonly assignedcopending application U.S. Ser. No. 07/687,326, filed Apr. 18, 1991, nowabandoned, which is a continuation-in-part of commonly-assignedcopending application U.S. Ser. No. 07/662,926, filed on Mar. 1, 1991,now abandoned.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention relates to 1H-imidazo[4,5-c]-quinoline compounds.In other aspects, this invention relates to antiviral1H-imidazo[4,5-c]quinolin-4-amines, intermediates for the preparation ofsuch compounds, pharmaceutical compositions containing such compounds,and pharmacological methods of using such compounds.

[0004] 2. Description of the Related Art

[0005] The first reliable report of the 1H-imidazo-[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950), describesthe synthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]-quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines have been-reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), hassynthesized the compound1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as a possibleanticonvulsant and cardiovascular agent. Also, Baranov et al., Chem.Abs. 85, 94362 (1976), has reported several2-oxoimidazo-[4,5-c]quinolines, and Berenyi et al., J. HeterocyclicChem. 18, 1537-1540 (1981), has reported certain2-oxoimidazo[4,5-c]-quinolines.

[0006] Certain antiviral 1H-imidazo[4,5-c]quinolin-4-amines aredescribed in U.S. Pat. No. 4,689,338 (Gerster). These compounds aresubstituted on the 1-position by alkyl, hydroxyalkyl, acyloxyalkyl,benzyl, phenylethyl or substituted phenylethyl, and at the 2-positionwith hydrogen, alkyl, benzyl, or substituted benzyl, phenylethyl orphenyl. Furthermore, these compounds are known to induce interferonbiosynthesis. Other antiviral 1H-imidazo[4,5-c]quinolin-4-amines,substituted on the 1-position by alkenyl substituents, are described inU.S. Pat. No. 4,929,624 (Gerster).

[0007] U.S. Pat. No. 4,698,348 (Gerster) discloses1H-imidazo[4,5-c]quinolines that are active as bronchodilators, such as4-substituted 1H-imidazo-[4,5-c]quinolines wherein the 4-substituent is,inter alia, hydrogen, chloro, alkylamino, or dialkylamino, and the2-substituent is, inter alia, hydroxyalkyl, aminoalkyl, oralkanamidoalkyl. Said patent also discloses 3-amino and 3-nitroquinoline intermediates substituted at the 4-position byhydroxyalkylamino or cyclohexylmethylamino, and1H-imidazo[4,5-c]quinoline N-oxide intermediates substituted at the2-position with, inter alia, hydroxyalkyl, aminoalkyl, oralkanamidoalkyl.

DETAILED DESCRIPTION OF THE INVENTION

[0008] This invention provides compounds of Formula I:

[0009] wherein R₁ is selected from the group consisting of: hydrogen;straight chain or branched chain alkyl containing one to about tencarbon atoms and substituted straight chain or branched chain alkylcontaining one to about ten carbon atoms, wherein the substituent isselected from the group consisting of cycloalkyl containing three toabout six carbon atoms and cycloalkyl containing three to about sixcarbon atoms substituted by straight chain or branched chain alkylcontaining one to about four carbon atoms; straight chain or branchedchain alkenyl containing two to about ten carbon atoms and substitutedstraight chain or branched chain alkenyl containing two to about tencarbon atoms, wherein the substituent is selected from the groupconsisting of cycloalkyl containing three to about six carbon atoms andcycloalkyl containing three to about six carbon atoms substituted bystraight chain or branched chain alkyl containing one to about fourcarbon atoms; hydroxyalkyl of one to about six carbon atoms; alkoxyalkylwherein the alkoxy moiety contains one to about four carbon atoms andthe alkyl moiety contains one to about six carbon atoms; acyloxyalkylwherein the acyloxy moiety is alkanoyloxy of two to about four carbonatoms or benzoyloxy, and the alkyl moiety contains one to about sixcarbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl,(phenyl)ethyl, or phenyl substituent being optionally substituted on thebenzene ring by one or two moieties independently selected from thegroup consisting of alkyl of one to about four carbon atoms, alkoxy ofone to about four carbon atoms, and halogen, with the proviso that ifsaid benzene ring is substituted by two of said moieties, then themoieties together contain no more than six carbon atoms;

[0010] R₂ and R₃ are independently selected from the group consisting ofhydrogen, alkyl of one to about four carbon atoms, phenyl, andsubstituted phenyl wherein the substituent is selected from the groupconsisting of alkyl of one to about four carbon atoms, alkoxy of one toabout four carbon atoms, and halogen;

[0011] X is selected from the group consisting of alkoxy containing oneto about four carbon atoms, alkoxyalkyl wherein the alkoxy moietycontains one to about four carbon atoms and the alkyl moiety containsone to about four carbon atoms, hydroxyalkyl of one to about four carbonatoms, haloalkyl of one to about four carbon atoms, alkylamido whereinthe alkyl group contains one to about four carbon atoms, amino,substituted amino wherein the substituent is alkyl or hydroxyalkyl ofone to about four carbon atoms, azido, chloro, hydroxy, 1-morpholino,1-pyrrolidino, and alkylthio of one to about four carbon atoms; and

[0012] R is selected from the group consisting of hydrogen, straightchain or branched chain alkoxy containing one to about four carbonatoms, halogen, and straight chain or branched chain alkyl containingone to about four carbon atoms;

[0013] or a pharmaceutically acceptable acid addition salt thereof.

[0014] This invention provides intermediate compounds of Formula V(a)

[0015] wherein R is as defined above, Y is —NO₂ or —NH₂, and R₄ isalkoxyalkyl wherein the alkoxy moiety contains one to about four carbonatoms and the alkyl moiety contains two to about six carbon atoms.

[0016] This invention provides intermediate compounds of Formula VII(a)

[0017] wherein R is as defined above in connection with Formula V(a) andR₄′ is alkoxy alkol wherein the alkoxy moiety contains one to about fourcarbon atoms and the alkyl moiety contains one to about six carbonatoms.

[0018] This invention provides intermediate compounds of Formula IX(a)

[0019] wherein R, R₂, and R₃ are as defined above;

[0020] R₅ is selected from the group consisting of: straight chain orbranched chain alkyl containing one to about ten carbon atoms andsubstituted straight chain or branched chain alkyl containing one toabout ten carbon atoms, wherein the substituent is selected from thegroup consisting of cycloalkyl containing three to about six carbonatoms and cycloalkyl containing three to about six carbon atomssubstituted by straight chain or branched chain alkyl containing one toabout four carbon atoms; straight chain or branched chain alkenylcontaining two to about ten carbon atoms and substituted straight chainor branched chain alkenyl containing two to about ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to about six carbon atoms and cycloalkylcontaining three to about six carbon atoms substituted by straight chainor branched chain alkyl containing one to about four carbon atoms;alkoxyalkyl wherein the alkoxy moiety contains one to about four carbonatoms and the alkyl moiety contains one to about six carbon atoms;acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to aboutfour carbon atoms or benzoyloxy, and the alkyl moiety contains one toabout six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl,(phenyl)ethyl, or phenyl substituent being optionally substituted on thebenzene ring by one or two moieties independently selected from thegroup consisting of alkyl of one to about four carbon atoms, alkoxy ofone to about four carbon atoms, and halogen, with the proviso that ifsaid benzene ring is substituted by two of said moieties, then themoieties together contain no more than six carbon atoms; and

[0021] G is selected from the group consisting of alkoxy containing oneto about four carbon atoms, alkoxyalkyl wherein the alkoxy moietycontains one to about four carbon atoms and the alkyl moiety containsone to about four carbon atoms, alkylamido wherein the alkyl groupcontains one to about four carbon atoms, azido, chloro, 1-morpholino,1-pyrrolidino, alkylthio of one to about four carbon atoms, alkanoyloxy,alkanoyloxyalkyl wherein the alkyl moiety contains one to about fourcarbon atoms, and aroyloxy, with the proviso that when G is alkylamidothen R₅ is alkenyl, substituted alkenyl, or alkoxyalkyl.

[0022] Further this invention provides compounds of Formula XI(a)

[0023] wherein R, R₂, R₃ and R₅ are as defined above,

[0024] Z is selected from the group consisting of alkoxy containing oneto about four carbon atoms, alkoxyalkyl wherein the alkoxy moietycontains one to about four carbon atoms and the alkyl moiety containsone to about four carbon atoms, hydroxyalkyl containing one to aboutfour carbon atoms, oxoalkyl containing two to about four carbon atoms,alkanoyloxyalkyl wherein the alkyl moiety contains one to about fourcarbon atoms, alkylamido wherein the alkyl group contains one to aboutfour carbon atoms, substituted amino wherein the substituent is alkyl orhydroxyalkyl of one to about four carbon atoms, azido, chloro,1-morpholino, 1-pyrrolidino, alkylthio of one to about four carbonatoms, hydroxy, alkanoyloxy, and aroyloxy; and

[0025] Q is selected from the group consisting of hydrogen, chloro, andR_(i)-E-NH— wherein R_(i) is an organic group substantially inert toquinoline N-oxides and E is a hydrolytically active functional group,with the proviso that when Q is R_(i)-E-NH—, then Z is other thanhydroxy, substituted amino, or hydroxyalkyl, and with the furtherproviso that when Q is hydrogen or chloro and Z is alkylamido orhydroxyalkyl, then Rs is alkenyl, substituted alkenyl, or alkoxyalkyl.

[0026] R₁ of Formula I preferably contains two to about ten carbonatoms. More preferably R₁ contains two to about eight carbon atoms. Mostpreferably, R₁ is 2-methylpropyl or benzyl.

[0027] X of Formula I is preferably azido, hydroxy, ethoxy, methoxy,1-morpholino, or methylthio, particularly in embodiments wherein R₁ is2-methylpropyl, 2-hydroxy-2-methylpropyl, or benzyl.

[0028] Other substituents in compounds of Formula I that contain analkyl radical (e.g., R when R is alkoxy or alkyl, or X when X isalkylamido) preferably contain two carbon atoms or, more preferably, onecarbon atom in each alkyl radical.

[0029] It is preferred that R of Formula I be hydrogen.

[0030] Most preferred compounds of Formula I include4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methanolhemihydrate,4-amino-_,_-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol,2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, and4-amino-1-phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methanol.

[0031] A compound of the invention can be prepared as described in theReaction Scheme below, wherein R, R₁, R₂, R₃, and X are as defined aboveand wherein P is a hydroxyl protecting group that can subsequently beremoved, such as alkanoyloxy (e.g., acetoxy), or aroyloxy (e.g.,benzoyloxy), and R₅ is as defined for R₁ above absent hydroxyalkyl andhydrogen.

[0032] Many quinolines of Formula III are known compounds (see, forexample, U.S. Pat. No. 3,700,674 and references cited therein). Thosethat are not known can be prepared by known methods, for example, from4-hydroxy-3-nitroquinolines as illustrated in step (1) of Scheme I. Step(1) can be conducted by reacting the 4-hydroxy-3-nitroquinoline ofFormula II with a chlorinating agent such as thionyl chloride orphosphorus oxychloride. The reaction is preferably conducted inN,N-dimethylformamide, optionally in the presence of methylene chloride,and is preferably accompanied by heating. Preferably, a large molarexcess of phosphorus oxychloride is avoided. Use of about 1-2 moles ofphosphorus oxychloride per mole of the 4-hydroxy-3-nitroquinoline ofFormula II has been found to be particularly preferable.

[0033] In step (2) a 3-nitro-4-chloroquinoline of Formula III is reactedby heating with an amine of the formula R₅NH₂, wherein R₅ is as definedabove, in a suitable solvent such as water, dichloromethane, ortetrahydrofuran, to provide a quinoline of Formula IV. Steps (1) and (2)can be combined such that the 3-nitro-4-chloroquinoline need not beisolated prior to reaction with the compound of the formula R₅NH₂. Sucha reaction is exemplified in Example 134 and Example 188 (Step A) ofU.S. Pat. No. 4,689,338, the disclosure of which is incorporated hereinby reference.

[0034] A compound of Formula IV is reduced in step (3) preferably usinga catalyst such as platinum on carbon, to provide a compound of FormulaV. This can be carried out conveniently on a Parr apparatus in an inertsolvent such as toluene or a lower alkanol.

[0035] In step (4) an intermediate compound of Formula V is reacted with(i) a carboxylic acid of the formula,

(OH)(R₂)(R₃)CCO₂H

[0036] or (ii) a trialkyl ortho ester of the formula,

(OH)(R₂)(R₃)C—C(OAlkyl)₃

[0037] wherein “alkyl” is a straight chain or branched chain alkyl groupcontaining one to about four carbon atoms, or (iii) a combination ofsuch a carboxylic acid with such a trialkyl ortho ester to provide acompound of Formula VI. In any case, the reaction can be carried out byheating, e.g., at about 130° C., in the presence of an acid, preferablya carboxylic acid of the formula

(OH)(R₃)(R₂)CCO₂H

[0038] An alternate method of providing the 2-substituted imidazo ringis illustrated in steps (5) and (6). Step (5) involves a reactionsimilar to that described in connection with step (4), but involvingformic acid or a trialkylorthoformate to form an intermediate of FormulaVII. The intermediate of Formula VII can then be deprotonated by astrong base (e.g., an alkyllithium such as n-butyllithium) and reactedwith a compound of the formula

[0039] to form an intermediate of Formula VI.

[0040] Step (7) involves protecting the hydroxyl group with a removableprotecting group such as an alkanoyloxy group (e.g., acetoxy) or anaroyloxy group (e.g., benzoyloxy). In instances wherein a hydroxyl groupis present in the 1-substituent, it too can be protected in step (7) andlater removed as appropriate when it will no longer interfere withsubsequent reactions. Suitable protecting groups and reactions for theirplacement and removal are well known to those skilled in the art. See,for example, U.S. Pat. No. 4,689,338 (Gerster), Examples 115-123.

[0041] Step (8) provides an intermediate of Formula IX, throughoxidation of a compound of Formula VIII with a conventional oxidizingagent that is capable of forming N-oxides. Preferred oxidizing agentsinclude peroxyacids and hydrogen peroxide. Heating is generally employedto accelerate the rate of reaction. In step (9) an N-oxide of Formula IXis heated in the presence of a suitable chlorinating agent such asphosphorus oxychloride to provide a chlorinated intermediate of FormulaX.

[0042] In step (10) the 4-chloro group is replaced by a 4-amino groupand the protecting group P is removed to provide a compound of FormulaXII (a subgenus of Formula I). The amination reaction is carried out inthe presence of ammonium hydroxide or, preferably, ammonia. Preferablythe intermediate of Formula X is heated at 125° to 175° C. underpressure for 6-24 hours. Preferably the reaction is conducted in asealed reactor in the presence of either ammonium hydroxide or asolution of ammonia in an alkanol, (e.g., preferably about 5% to about15% ammonia in methanol).

[0043] A compound of Formula XII can also be prepared by way of step(9a) of the Reaction Scheme. Step (9a) involves (i) reacting a compoundof Formula IX with an acylating agent; (ii) reacting the product with anaminating agent; and (iii) isolating the compound of Formula XII. Part(i) of step (9a) involves reacting an N-oxide with an acylating agent.Suitable acylating agents include alkyl- or arylsulfonyl chlorides(e.g., benzenesulfonyl chloride, methanesulfonyl chloride,p-toluenesulfonyl chloride). Arylsulfonyl chlorides are preferred.p-Toluenesulfonyl chloride is most preferred. Part (ii) of step (9a)involves reacting the product of part (i) with an excess of an aminatingagent. Suitable aminating agents include ammonia (e.g., in the form ofammonium hydroxide) and ammonium salts (e.g., ammonium carbonate,ammonium bicarbonate, and ammonium phosphate). Ammonium hydroxide ispreferred. The reaction of step (9a) is preferably carried out bydissolving the N-oxide of Formula IX in an inert solvent such asmethylene chloride, adding the aminating agent to the solution, and thenadding the acylating agent. Preferred conditions involve cooling toabout 0° C. to about 5° C. during the addition of the acylating agent.Heating or cooling can be used to control the rate of the reaction. Step(9a) also involves removal of protecting group P as discussed above inconnection with step (7). A further alternative method of preparing acompound of Formula XII is shown in steps (11) and (12).

[0044] Step (11) involves reacting an N-oxide with an isocyanate whereinthe isocyanato group is bonded to a hydrolytically active functionalgroup. The term “hydrolytically active functional group” as used hereindesignates any functional group that is capable of being subjected to anucleophilic displacement reaction in step (12) of the Reaction Scheme.Exemplary hydrolytically active functional groups include carbonyl

[0045] A particular class of such isocyanates is isocyanates of theformula R_(i)-E-NCO, wherein R_(i) is an organic group substantiallyinert to quinoline N-oxides under the conditions of step (11) and E is ahydrolytically active functional group. Suitable R_(i) groups are easilyselected by those skilled in the art. Preferred groups R_(i) includealkyl, aryl, alkenyl, and combinations thereof. Particular preferredisocyanates include aroyl isocyanates such as benzoylisocyanate. Thereaction of the isocyanate with the N-oxide is carried out undersubstantially anhydrous conditions by adding the isocyanate to asolution of the N-oxide in an inert

[0046] solvent such as dichloromethane. The resulting 4-substitutedcompound of Formula XI can be isolated by removal of the solvent.

[0047] Step (12) of the Reaction Scheme involves hydrolysis of acompound of Formula XI. The term “hydrolysis” as used herein designatesnot only nucleophilic displacement with water but also displacement withother nucleophilic compounds. Such a reaction can be carried out bygeneral methods well known to those skilled in the art, e.g., by heatingin the presence of a nucleophilic solvent such as water or a loweralkanol optionally in the presence of a catalyst such as an alkali metalhydroxide or lower alkoxide.

[0048] In steps (9a), (10) or (12) a compound comprising a protectinggroup such as acetoxy, benzoyloxy, or the like, is deprotected to afforda compound comprising a hydroxyl group. A hydroxyl-containing compoundof Formula I can be converted or elaborated by methods well known to theskilled in the art to afford a further compound of Formula I. Forexample, reaction with thionyl chloride will provide a compound ofFormula I wherein X is chloro. Reaction of this compound with anucleophile such as sodium azide, pyrrolidine, methanethiol, ormorpholine will afford a compound of Formula I wherein X is azido,1-pyrrolidino, thiomethyl, or 1-morpholino, respectively. Reduction ofan azido compound provides a compound of Formula I wherein X is amino.Such an amino compound can be acylated to form a compound wherein X isalkylamido.

[0049] Some compounds of Formula I can be prepared by a similar reactionscheme wherein the group X is introduced directly in step (4) in whichcase hydroxyalkyl substituents will be tolerated at the 1-position withappropriate use of the various protection and deprotection steps.

[0050] Substituents at the 2-position can be introduced by reacting acompound of Formula XIII

[0051] wherein R and R₅ are as defined above, with a lithiating agentsuch a lithium diisopropylamide or n-butyllithium in a polar aproticsolvent to afford a compound lithiated on the 2-methyl group. Thelithiated compound can then be reacted with an appropriate reagentcontaining a leaving group capable of being displaced by the lithiated2-methyl group, such as, e.g., chloromethylmethylether orN-methoxy-N-methylacetamide, in order to elaborate the 2-methyl group.Such compounds can then be carried on as appropriate to compounds ofFormula I.

[0052] A further alternate process for preparing certain compounds ofFormula I involves as a first step the preparation of a3-amino-4-(substituted)amino-2-chloroquinoline according to the methodset forth in U.S. Pat. No. 4,988,815 (Andre et al., incorporated hereinby reference). This compound is then reacted in a polar aprotic solventwith a carboxylic acid halide, which reacts at the 3-amino group toafford the corresponding3-carboxamido-4-(substituted)amino-2-chloroquinoline. This compound isthen reacted with ammonia, e.g., in a hydroxylic solvent such asmethanol, at an elevated temperature (e.g., 100-150° C.) to effect 1)cyclization and 2) amination at the 4-position, resulting in a1-substituted, 2-substituted 1H-imidazo[4,5-c]quinolin-4-amine.

[0053] While not all compounds of Formula I can be prepared by theillustrated reaction scheme, known schemes can be easily adapted bythose skilled in the art in order to prepare compounds other than thoseexemplified herein. For example, compounds wherein R₁ is alkenyl can beprepared using the general schemes or adaptations thereof set forth inU.S. Pat. No. 4,929,624 (Gerster et al.) and compounds wherein R₁ ishydrogen can be prepared using the general schemes or adaptationsthereof set forth in commonly assigned copending application Ser. No.07/484,761 (Gerster), both being incorporated herein by reference. Afurther synthetic scheme that can be used by those skilled in the art inthe preparation of some of the compounds of the invention is disclosedin U.S. Pat. No. 4,988,815 (Andre' et al.) incorporated herein byreference. Further, those skilled in the art will recognize thatalteration of reaction sequence and utilization of conventionalsynthetic alternatives will allow the preparation of the compounds ofthe invention not amenable to the illustrated scheme.

[0054] The product compound of Formula I can be isolated by theconventional means disclosed in U.S. Pat. No. 4,689,338 (Gerster), suchas, for example, removal of the solvent and recrystallization from anappropriate solvent (e.g., N,N-dimethylformamide) or solvent mixture, orby dissolution in an appropriate solvent (such as methanol) andre-precipitation by addition of a second solvent in which the compoundis insoluble.

[0055] A compound of Formula I can be used as an antiviral agent itselfor it can be used in the form of a pharmaceutically acceptableacid-addition salt such as a hydrochloride, dihydrogen sulfate,trihydrogen phosphate, hydrogen nitrate, methanesulfonate or a salt ofanother pharmaceutically acceptable acid. A pharmaceutically acceptableacid-addition salt of a compound of Formula I can be prepared, generallyby reaction of the compound with an equimolar amount of a relativelystrong acid, preferably an inorganic acid such as hydrochloric,sulfuric, or phosphoric acid, or an organic acid such as methanesulfonicacid, in a polar solvent. Isolation of the salt is facilitated by theaddition of a solvent, such as diethyl ether, in which the salt isinsoluble.

[0056] A compound of the invention can be formulated for the variousroutes of administration in a pharmaceutically acceptable vehicle, suchas water or polyethylene glycol, along with suitable adjuvants,excipients, and the like. Particular formulations will be easilyselected by those skilled in the art. Suitable formulations for topicalapplication include creams, ointments and like formulations known tothose skilled in the art. Formulations generally contain less than 10%by weight of a compound of Formula I, preferably about 0.1% to 5% byweight of a compound of Formula I.

[0057] The compounds of Formula I exhibit antiviral activity in mammals.They can therefore be used to control viral infections. For example, acompound of Formula I can be used as an agent to control infections inmammals caused by Type II Herpes simplex virus. Compounds of Formula Ican also be used to treat a herpes infection by oral, topical, orintraperitoneal administration.

[0058] A number of compounds of Formula I were tested and found toinduce biosynthesis of interferon in human cells and in mice.Furthermore, a number of compounds of Formula I were tested and found toinhibit tumors in mice. The test methods and results are set forthbelow. These results suggest that at least certain compounds of theinvention might be useful in treating other diseases such as rheumatoidarthritis, warts, eczema, Hepatitis B, psoriasis, multiple sclerosis,essential thrombocythaemia, cancer such as basal cell carcinoma, andother neoplastic diseases.

[0059] In the following Examples, all reactions were run with stirringunder an atmosphere of dry nitrogen unless otherwise indicated. Theparticular materials and amounts thereof recited in the Example, as wellas other conditions and details, should not be construed to unduly limitthe invention.

EXAMPLE 1 1-(2-Methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methanol

[0060] 3-Nitro-4-(2-methylpropylamino)quinoline (36.8 g; 0.15 mol) wasadded to a mixture of ethyl acetate (300 mL), 5% Pt/C (about 1 g), andmagnesium sulfate (30 g). The mixture was hydrogenated at about 50 psiinitial pressure. When hydrogenation was complete the solids werefiltered from the mixture and the ethyl acetate was evaporated. Theresulting intermediate diamine was mixed with glycolic acid (26.9 g;0.35 mol) and the mixture was heated at 150-160° C. for about 3 hr withoccasional manual stirring. The reaction mixture was then dissolved indilute hydrochloric acid and treated with decolorizing carbon, and thesolids were filtered from the mixture. The filtrate was made basic withammonium hydroxide to precipitate the product as a greenish solid. Thesolid was filtered and dried to give 34.3 g (89.6%) of crude product.The solid was reprecipitated a second time as above and the productrecrystallized from ethyl acetate to give greenish crystals, m.p.165-168° C. Analysis: Calculated: C, 70.6; H, 6.7; N, 16.5. Found: C,70.4; H, 6.7; N, 16.3.

EXAMPLE 2 1-(2-Methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methylAcetate

[0061] 1-(2-Methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methanol (51.4g; 0.2 mol, Example 1) was dissolved in dichloromethane (500 mL)containing triethylamine (30.9 mL; 0.22 mol). The solution was stirredat room temperature while acetyl chloride was added dropwise. Theresulting solution was stirred at room temperature for about 24 hr andthen washed with water and aqueous sodium bicarbonate. The organic layerwas dried over magnesium sulfate and evaporated to yield 58.1 g (97%) ofthe acetate as a brownish solid. The product was recrystallized fromethyl acetate to give a tan solid m.p. 147-154° C. Analysis: Calculated:C, 68.7; H, 6.4; N, 14.1. Found: C, 68.1; H, 6.4; N, 13.8.

EXAMPLE 3 1-(2-Methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methylBenzoate

[0062] The compound was prepared from1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (Example 1)using benzoyl chloride in the general method of Example 2.

EXAMPLE 4 2-Acetoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide

[0063] 1-(2-Methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methyl acetate(63.0 g; 0.21 mol, Example 2) was suspended in ethanol (475 mL) and 32%peracetic acid (89 mL; 0.42 mol) was added to the mixture. The mixturewas heated at 50° C. with stirring for 2 hr. The solid dissolved uponheating and after about 1½ hr a heavy precipitate formed. Theprecipitate was filtered from the mixture and dried to yield 33.7 g ofthe N-oxide. The filtrate was concentrated to 100 mL and an additional15.2 g of solid was collected. A total crude yield of 48.9 g (74.3%) wasobtained. The material was recrystallized from ethanol to give paleyellow crystals m.p. 233-240° C. Analysis: Calculated: C, 65.1; H, 6.1;N, 13.4. Found: C, 64.6; H, 6.1; N, 13.2.

EXAMPLE 52-Benzoyloxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0064] The compound was prepared using1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methyl benzoate (Example3) in the method of Example 4 and recrystallized from ethyl acetate togive a pure product, m.p. 192-195° C. Analysis: Calculated: C, 70.4; H,5.6; N, 11.2. Found: C, 70.6; H, 5.7; N, 11.2.

EXAMPLE 64-Chloro-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methyl Acetate

[0065] 2-Acetoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5Noxide (48.9 g; 0.156 mol, Example 4) was suspended in dichloromethane(500 mL) and phosphorous oxychloride (17.5 mL; 0.187 mol) was addeddropwise to the stirred suspension. The vigorous reaction was controlledby adjusting the rate of addition. When addition was complete themixture was stirred at reflux for 1 hr. The mixture was then cautiouslyneutralized with sodium bicarbonate. All solid dissolved in thedichloromethane. The organic layer was separated, dried over magnesiumsulfate, and evaporated to yield 43.6 g (84.2%) of crude product. Asmall amount was purified by silica gel flash chromatography (ethylacetate as eluent) and recrystallized from ethyl acetate to give a puresample m.p. 182-188° C. Analysis: Calculated: C, 61.5; H, 5.5; N, 12.7.Found: C, 61.5; H, 5.4; N, 12.6.

EXAMPLE 74-Chloro-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylBenzoate

[0066] The compound was prepared using2-benzoyloxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-5N-oxide(Example 5) in the method of Example 6 and recrystallized from ethylacetate/hexane for analysis and characterization. m.p. 143-150° C.Analysis: Calculated: C, 67.1; H, 5.1; N, 10.7. Found: C, 67.2; H, 5.1;N, 10.6.

EXAMPLE 84-Chloro-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol

[0067] 4-Chloro-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylbenzoate (14.3 g; 0.36 mol, Example 7) was suspended in dry methanol(350 mL). The mixture was made basic (pH 10) with 25% sodium methoxide.The mixture was stirred at room temperature for 5 hr after which timeonly a trace of starting material was detected by silica gel TLC (ethylacetate eluent). The mixture was made acidic with acetic acid and thenconcentrated to dryness. The residue was slurried in ether. The solidwas filtered from the mixture and then suspended in aqueous sodiumhydroxide. The product was filtered from the mixture, washed with water,and dried to yield 7.5 g (71.4%) of tan solid. The product wasrecrystallized from ethanol to yield 4.8 g of pure product m.p. 162-166°C. Analysis: Calculated: C, 62.2; H, 5.6; N, 14.5. Found: C, 62.2; H,5.6; N, 14.3.

EXAMPLE 94-Amino-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol

[0068] 4-Chloro-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylbenzoate (5.0 g; 0.13 mol, Example 7) was added to 15% methanolicammonia (50 mL). The mixture was heated in a Parr bomb for 7 hr at 175°C. The resulting solution was evaporated to reduce the volume. A stickysolid crystallized from the solution. The solid was filtered from themixture and slurried in aqueous sodium bicarbonate solution. Theresulting solid was filtered from the mixture, washed with water, anddried to yield 2.1 g (61.7%) of crude product which was recrystallizedfrom ethanol several times to yield pure product m.p. 226-231° C.Analysis: Calculated: C, 66.6: H, 6.7; N, 20.7. Found: C, 66.4; H, 6.5;N, 20.4.

EXAMPLE 102-Chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amineHydrochloride

[0069] 4-Amino-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol(5.0 g; 0.0185 mol, Example 9) was added in small portions to vigorouslystirred thionyl chloride (25 mL). The resulting mixture was stirred atroom temperature overnight. The mixture was diluted with 100 mL ofether, and the solid was filtered from the mixture and dried thoroughly.The product was pure enough for further reactions. A sample wasrecrystallized from ethanol to give a pure product which melted withdecomposition from 279-292° C. Analysis: Calculated: C, 55.4; H, 5.6; N,17.2. Found: C, 55.3; H, 5.5; N, 17.1.

EXAMPLE 112-Azidomethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinolin-4-amine

[0070]2-Chloromethyl-1(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (2.5 g; 0.0077 mol, Example 10) was suspended inN-methylpyrrolidone (15 mL). A solution of lithium azide (2.3 g) inwater (45 mL) was added to the suspension. The resulting mixture washeated on the steam bath for 2 hr and then diluted with water (about 45mL). The tan solid was washed with water and dried to yield 1.4 g(60.9%) of crude product. The solid was recrystallized from ethanol togive a pure product m.p. 174-178° C. Analysis: C, 61.0; H, 5.8; N, 33.2.Found: C, 60.9; H, 5.6; N, 32.6.

EXAMPLE 121-(2-Methylpropyl)-2-morpholinomethyl-1H-imidazo-[4,5-c]quinolin-4-amine

[0071]2-Chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (Example 10, prepared from 2.0 g of the correspondingalcohol) was added to morpholine (5 mL). The mixture was refluxed for 4hr. The resulting solution was cooled to room temperature. A solidprecipitated. The solid was filtered from the mixture and slurried inaqueous sodium bicarbonate solution. The product was filtered from themixture, washed with water, and dried to yield 1.7 g (68.0%) of solid,which was recrystallized from ethanol to give a pure product m.p.228-234° C. Analysis: Calculated: C, 67.2; H, 7.4; N, 20.6. Found: C,67.3; H, 7.9; N, 20.6.

EXAMPLE 131-(2-Methylpropyl)-2-pyrrolidinomethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0072] The pyrrolidinomethyl compound was prepared from2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-aminehydrochloride (Example 10) by substituting pyrrolidine for morpholine inthe method of Example 12. A crude yield of 1.90 g (63.3%) was obtained.Recrystallization of the crude solid from ethanol gave the pure product.m.p. 172-187° C. Analysis: Calculated: C, 70.6; H, 7.8; N, 21.7. Found:C, 70.6; H, 7.8; N, 21.5.

EXAMPLE 144-Amino-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanamine

[0073] 2-Azidomethyl-1(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine(3.2 g, 0.0108 mol, Example 11) was added to ethanol (300 mL) and 5%Pd/C (about 1 g) was added to the mixture. The mixture was hydrogenatedon a Parr apparatus until hydrogen uptake stopped. Hydrogen was removedand the mixture was flushed with hydrogen to regenerate the catalyst.Hydrogenation was resumed. This procedure was repeated until no morehydrogen was absorbed. The catalyst was filtered from the mixture andthe filtrate was evaporated. The residue was recrystallized severaltimes from ethanol to give yellowish crystals m.p. 287-291° C. Analysis:Calculated: C, 66.9; H, 7.1; N, 26.0. Found: C, 66.5; H, 7.2; N, 25.1.

EXAMPLE 15N-Acetyl-4-amino-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanamine

[0074]4-Amino-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanamine(1.1 g; 0.004 mol, Example 14) was added to acetic anhydride (3 mL). Themixture was stirred at room temperature for 5 hrs. The solution was thendiluted with methanol (50 mL) and refluxed for 1 hr. The solution wasconcentrated and the residue made basic with aqueous sodium bicarbonatesolution. The oily residue was extracted into dichloromethane. Theextracts were dried over magnesium sulfate and evaporated to dryness.The residue was recrystallized from ethyl acetate to yield pure productm.p. 214-218° C. Analysis: Calculated: C, 65.6; H, 6.8; N, 22.5. Found:C, 65.1; H, 6.6; N, 22.0.

EXAMPLE 16α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol

[0075] 3-Amino-4-(2-methylpropylamino) quinoline (29.0 g; 0.135 mol) andlactic acid (36 mL; 0.48 mol) were mixed and heated at 140° C. for 6 hr.The mixture was then dissolved in dilute hydrochloric acid and treatedwith charcoal. The solids were filtered from the mixture. The filtratewas made basic with ammonium hydroxide to precipitate the product as anoil. The oil was extracted into ethyl acetate. The ethyl acetatesolution was treated with decolorizing carbon and the solids werefiltered from the mixture. The filtrate was evaporated to dryness toyield a greenish oil which was pure enough for further reactions. Asmall sample was triturated with hexane to obtain a solid which wasrecrystallized from ethyl acetate for analysis. m.p. 152-166° C.Analysis: Calculated: C, 71.4; H, 7.11; N, 15.6. Found: C, 71.1; H,7.33; N, 15.4.

EXAMPLE 17α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylBenzoate

[0076]α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol (20.0g; 0.074 mol, Example 16) was dissolved in dichloromethane (200 mL) andtriethylamine (11.4 mL; 0.082 mol) was added to the solution. Benzoylchloride (9.5 mL; 0.082 mol) was added dropwise to the stirred solution.The mixture was stirred at room temperature for 6 hr. The solution waswashed with water and aqueous sodium bicarbonate solution, dried overmagnesium sulfate and evaporated to yield 26.6 g of greenish, viscousoil. The product was pure enough for the following N-oxidation step buta small sample was purified by silica gel flash chromatography (ethylacetate eluent) for analysis and characterization. m.p. 158-163° C.Analysis: Calculated: C, 74.0; H,.6.2; N, 11.3. Found: C, 73.7; H, 6.2;N, 11.2.

EXAMPLE 18α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylBenzoate 5N Oxide

[0077] α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylbenzoate (11.7 g; 0.031 mol, Example 17) was added to ethanol and 32%peracetic acid (11.1 mL; 0.0092 mol) was added to the solution. Themixture was heated at 65° C. for 5 hr. The solution was then evaporatedto dryness. The residue was treated with aqueous sodium bicarbonatesolution. The product was extracted into ethyl acetate, dried overmagnesium sulfate, and evaporated to yield an oily residue containing atrace of starting material. The crude product was used in subsequentreactions.

EXAMPLE 194-Chloro-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylBenzoate

[0078] α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylbenzoate 5N oxide (9.2 g; 0.0236 mol, Example 18) was added todichloromethane (200 mL). Phosphorous oxychloride (2.6 mL; 0.0283 mol)was added to the solution. The reaction mixture was stirred at roomtemperature for 2½ hr. The solution was evaporated and the residue wasmixed with water and ammonium hydroxide. The oil was extracted intoethyl acetate. The extracts were dried over magnesium sulfate andevaporated to dryness. A yield of 7.6 g (79.2%) of product was obtainedas a glassy solid, which was used as such for the next reaction.

EXAMPLE 204-Amino-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0079]4-Chloro-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylbenzoate (3.7 g; 0.009 mol, Example 19) was added to 15% methanolicammonia (50 mL). The mixture was heated in a Parr bomb at 165° C. for 6hr. The resulting reaction mixture was evaporated and the residue wasslurried in aqueous sodium bicarbonate. The product was extracted intodichloromethane, and the extracts were washed with aqueous sodiumbicarbonate and dried over magnesium sulfate. The organic extracts wereevaporated to dryness to yield an oily solid. The solid was purified bysilica gel column chromatography to yield two products, the intendedproduct and the 4-(N-methyl) derivative. The intended product(R_(f)=0.36 silica gel TLC, ethyl acetate eluent) was recrystallizedfrom ethanol to yield a solid m.p. 190-195° C. Analysis: Calculated: C,67.6; H, 7.1; N, 19.7. Found: C, 67.6; H, 7.1; N, 19.7. The 4-(N-methyl)derivative was recrystallized from ethyl acetate to give a solid, m.p.145-149° C. Analysis: Calculated: C, 68.4; H, 7.4; N, 18.8. Found: C,68.3; H, 7.4; N, 18.7.

EXAMPLE 21α,α-Dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol

[0080] 3-Amino-4-(2-methylpropyl amino) quinoline (28.7 g; 0.133 mol)and 2-hydroxyisobutyric acid (27.8 g; 0.267 mol) were mixed and themixture was heated at 160° C. for 5 hrs. Water was added to the darkmixture and a green oil formed. The oil was extracted with ether toyield 8.6 g of an oil which contained two products. The mixture waspurified by silica gel column chromatography to yield 3.2 g of theintended product. A small amount was recrystallized from ethyl acetatefor analysis and characterization. m.p. 156-164° C. Analysis:Calculated: C, 72.1; H, 7.5; N, 14.8. Found: C, 71.9; H, 7.4; N, 14.6.

EXAMPLE 224-Chloro-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0081]α,α-Dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol(3.0 g; 0.0106 mol, Example 21) was dissolved in ethanol (30 mL) and 32%peracetic acid (3.8 mL; 0.0108 mol) was added. The mixture was heated at65° C. for 4 hr. The solution was concentrated and the residue wasslurried in aqueous sodium bicarbonate solution. The oily product wasextracted into ethyl acetate. The extracts were dried over magnesiumsulfate and evaporated to dryness. A yield of 2.8 g of N oxide as ayellow solid was obtained. The intermediate N oxide was added todichloromethane and 1.1 eq of phosphorous oxychloride was added to thevigorously stirred mixture. The mixture was stirred at room temperatureovernight and then concentrated. The residue was slurried in aqueoussodium bicarbonate and extracted into ethyl acetate. The product waspurified by silica gel flash chromatography (10% ethyl acetate indichloromethane). A small amount was recrystallized from ethyl acetateto give a solid, m.p. 205-210° C. Analysis: C, 64.2; H, 6.3; N, 13.2.Found: C, 64.2; H, 6.3; N, 13.1.

EXAMPLE 234-Amino-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0082]4-Chloro-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol(Example 22) was aminated in a Parr bomb at 150° C. using 15% methanolicammonia. The product was purified by silica gel column chromatography(5% methanol in ethyl acetate as eluent). The product was thenrecrystallized from ethyl acetate/hexane to give a solid, m.p. 214-217°C. Analysis: Calculated: C, 68.4; H, 7.4; N, 18.8. Found: C, 68.2; H,7.4; N, 18.7.

EXAMPLE 24 1-Phenylmethyl-1H-imidazo[4,5-c]-quinoline-2-methanol

[0083] 3-amino-4-(benzylamino) quinoline (9.5 g; 0.038 mol) and glycolicacid (6.8 g; 0.089 mol) were mixed and the mixture was heated at 150° C.for about 4 hr. The dark mixture was then dissolved in dilutehydrochloric acid with heating. Upon cooling a precipitate formed andwas filtered from the mixture. The solid was dissolved in hot water. Thesolution was then made basic with ammonium hydroxide to precipitate theproduct. A second, less pure, small crop was obtained from the originalfiltrate by making it basic with ammonium hydroxide. The solid wastriturated in ethyl acetate to give a green colored powder. Total yieldwas 82%. The product was recrystallized from methanol to give a puresample m.p. 211-213° C. Analysis: Calculated: C, 74.7; H, 5.2; N, 14.5.Found: C, 74.4; H, 5.1; N, 14.4.

EXAMPLE 25 1-Phenylmethyl-1H-imidazo[4,5-c]-quinoline-2-methyl Acetate

[0084] 1-Phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methanol (7.5 g;0.026 mol, Example 24) was added to dichloromethane (70 mL). Aceticanhydride (5.7 mL) and pyridine (3.1 mL) were added to the mixture. Themixture was refluxed for about 6 hr and the solids were then filteredfrom the mixture. The filtrate was evaporated and the residue wasfiltered, slurried consecutively in water and methanol/water. The solidwas then filtered from the mixture and dried to yield 6.7 g (74.4%) ofproduct. The solid was recrystallized from methanol. m.p. 216-218° C.Analysis: C, 72.5; H, 5.2; N, 12.7. Found: C, 72.1; H, 5.1; N, 12.6.

EXAMPLE 26 1-Phenylmethyl-1H-imidazo[4,5-c]-quinoline-2-methyl Acetate5N Oxide

[0085] 1-Phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methyl acetate (6.7g; 0.019 mol, Example 25) and 32% peracetic acid (4.6 mL; 0.0214 mol)were added to a mixture of ethyl acetate (125 mL) and ethanol (250 mL).The mixture was refluxed for 6 hr. The solution was evaporated todryness and the residue was slurried with aqueous sodium bicarbonatesolution. The solid was filtered from the mixture, washed with water,and dried to yield 7.2 g of crude product. The crude product wasrecrystallized from ethyl acetate. m.p. 229-232° C. Analysis:Calculated: C, 69.2; H, 4.9; N, 12.1. Found: C, 69.1; H, 4.9; N, 12.0.

EXAMPLE 27 4-Amino-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline-2-methanol

[0086] 1-Phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methyl acetate 5Noxide (5.6 g; 0.0162 mol, Example 26) was suspended in a mixture ofdichloromethane (150 mL) and ammonium hydroxide (55 mL). The mixture wascooled to 0-5° C. A solution of p-toluenesulfonyl chloride (3.4 g;0.0178 mol) in dichloromethane (25 mL) was added dropwise to thevigorously stirred mixture while maintaining the temperature at 0-5° C.When the addition was complete the mixture was allowed to stir at roomtemperature overnight. The dichloromethane was then evaporated from themixture and the solid was filtered from the mixture. The tan solid waswashed with water and dried to yield 5.5 g of product which was found tobe the acetate of the intended product. The acetate was added to amixture of-methanol (300 mL) and dichloromethane (100 mL). The mixturewas made basic with 25% methanolic sodium methoxide. After about ½ hrthe product began to precipitate from solution. The solid was filteredfrom the mixture, washed sequentially with water and methanol, and driedto yield 3.1 g (64.6%). A sample was recrystallized frommethanol/dichloromethane. m.p. >300° C. Analysis: Calculated: C, 71.0;H, 5.3; N, 18.4. Found: C, 71.1, H, 5.0; N, 18.1.

EXAMPLE 282-Chloromethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-amineHydrochloride

[0087] 4-Amino-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline-2-methanol(2.0 g; 0.0066 mol, Example 27) was added in small portions to thionylchloride (10 mL). After stirring at room temperature for 30 min theproduct had crystallized from solution. The mixture was diluted with dryether (75 mL). The solid was filtered from the mixture, washed withether, and thoroughly dried. The product was used as such withoutfurther characterization or purification.

EXAMPLE 292-Morpholinomethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-amine

[0088] 2-Chloromethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-aminehydrochloride (Example 28, prepared from 2.0 g of the alcohol) was addedto morpholine (5.0 mL) and the mixture was refluxed for 4 hr. Themixture was then cooled to room temperature and the solid was filteredfrom the mixture. The solid was slurried in aqueous sodium bicarbonatesolution, filtered from the mixture, and dried. A crude yield of 2.0 gof product as a white solid was obtained. The crude product wasrecrystallized from methanol/dichloromethane. m.p. >300° C. Analysis:Calculated: C, 70.7; H, 6.2; N, 18.8. Found: C, 70.4; H, 6.2; N, 18.6.

EXAMPLE 304-Amino-N-hydroxyethyl-N-methyl-1-phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methanamineHemihydrate

[0089] 2-Chloromethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-aminehydrochloride (Example 28, prepared from 1.4 g of the alcohol) was addedto N-methylethanolamine (20 mL). The mixture was heated in an oil bathfor 3 hr at about 130° C. The solution was diluted with water and themixture extracted with diethyl ether (7×200 mL). The combined extractswere washed with saturated sodium chloride solution and evaporated todryness to yield an orange solid. The crude product was recrystallizedfrom methanol/dichloromethane. m.p. 188-195° C. Analysis: Calculated: C,68.1; H, 6.5; N, 18.9. Found: C, 68.4; H, 6.5: N, 18.7.

EXAMPLE 312-Methylthiomethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-amine

[0090] 2-Chloromethyl-1-phenylmethyl-1H-imidazo-[4,5-c]quinolin-4-aminehydrochloride (Example 28, prepared from 2.11 g of the alcohol) wasadded to a solution of methanethiol (1.33 g; 0.028 mol) and sodiummethoxide (1.5 g; 0.028 mol) in methanol. The solid dissolved uponaddition and a cream colored solid precipitated during addition. Afterstirring at room temperature for several hours the mixture was dilutedwith water. The solid was filtered from the mixture, washed with water,and dried. A crude yield of 2.3 g was obtained. The product was purifiedby silica gel flash chromatography (10% methanol in ethyl acetateeluent) and recrystallized from methanol/dichloromethane to give a creamcolored solid, m.p. 217-219° C. Analysis: Calculated: C, 68.2; H, 5.4;N, 16.8. Found: C, 67.5; H, 5.3; N, 16.6.

EXAMPLE 32 2-Methoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

[0091] 3-Amino-4-(2-methylpropylamino)quinoline (5.0 g; 0.023 mol) andmethoxyacetic acid (20 mL) were mixed and heated at about 200° C. untilall bubbling had stopped. Heating was continued for 5-10 min longer andthe dark solution was allowed to cool to room temperature. The solutionwas diluted with water, made strongly basic with 50% sodium hydroxideand extracted with ether. The combined extracts were dried overmagnesium sulfate and evaporated to dryness to yield 5.2 g of crudeproduct. The crude product was used as such for further reactions. Asmall sample was recrystallized from ether to yield nearly colorlesscrystals, m.p. 96-99° C. Analysis: Calculated: C, 71.4; H, 7.1; N, 15.6.Found: C, 71.1; H, 7.0; N, 15.6.

EXAMPLE 33 2-Methoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide Monohydrate

[0092] 2-Methoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline(5.0 g; 0.0186 mol, Example 32) was added to ethyl acetate (100 mL)containing 32% peracetic acid (4.9 g; 0.0206 mol). The solution wasrefluxed for about 15 min. The solution was then evaporated. The residuewas slurried in aqueous sodium bicarbonate and the solid was filteredfrom the mixture. A second crop was obtained by allowing the filtrate tostand overnight at room temperature. A combined yield of 4.6 g (86.8%)of crude product was obtained. A pure sample was obtained byrecrystallized from isopropyl alcohol. m.p. broad; Analysis: Calculated:C, 63.5; H, 7.0; N, 13.8. Found: C, 63.5; H, 6.7; N, 13.8.

EXAMPLE 342-Methoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0093] 2-Methoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5Noxide (4.0 g; 0.014 mol, Example 33) was dissolved in dichloromethane(80 mL). Concentrated ammonium hydroxide (30 mL) was added to thesolution. The mixture was cooled to 0-5° C. and vigorously stirred as asolution of p-toluenesulfonyl chloride (2.9 g; 0.015 mol) indichloromethane (15 mL) was added dropwise. The temperature wasmaintained at 0-5° C. during addition. When addition was complete themixture was stirred at room temperature for 1 hr. The dichloromethanewas separated from the aqueous layer, dried over magnesium sulfate, andevaporated to dryness to yield 1.7 g of a tan powder. Tworecrystallizations from isopropyl alcohol gave an analytically puresample, m.p. 157-160° C. which analyzes for a quarter mole of water.Analysis: Calculated: C, 66.5; H, 7.2; N, 19.4. Found: C, 66.9; H, 6.9;N, 19.0.

EXAMPLE 35 1-(2-Methoxyethyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline

[0094] 4-(2-Methoxyethylamino)-3-nitroquinoline (16.24 g; 0.066 mol) wasadded to a mixture of ethyl acetate (1500 mL), 5% platinum on carbon (1g), and magnesium sulfate (6 g). The mixture was hydrogenated on a Parrapparatus at 30 psi initial pressure. When the hydrogenation wascomplete, the solids were filtered off and the ethyl acetate wasevaporated. The resulting diamine intermediate was heated withmethoxyacetic acid (70 mL) at 150° C. for 2-3 hours and then at 120° C.for 2-3 hours. The reaction mixture was poured into water (400 mL), madestrongly basic with 6N sodium hydroxide and then extracted with ether(3×200 mL). The ether extracts were combined, washed with brine thenevaporated to provide 9.9 g of an oil which crystallized on standing.The aqueous layers were extracted again with ether (4×200 mL). Theextracts were combined, washed with brine and evaporated. The residuewas recrystallized from ethyl acetate to provide 1.5 g yellow needles.Analysis: Calculated: C, 66.4; H, 6.3; N, 15.5; Found: C, 66.6; H, 6.4;N, 16.1.

EXAMPLE 36 1-(2-Methoxyethyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline5N Oxide

[0095] 1-(2-Methoxyethyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline(13.3 g, 0.044 mol, Example 35) was dissolved in warm ethyl acetate (150mL) and 32% peracetic acid (12.0 mL) was slowly added to the solution.The mixture was heated at reflux for 2-3 hours and then allowed to standat room temperature overnight. The resulting precipitate was collected,rinsed with ethyl acetate then coevaporated with toluene to yield 2.6 gof a solid. The ethyl acetate filtrate was evaporated. The resultingresidue was taken up in about 300 mL of water and made basic withconcentrated ammonium hydroxide. The resulting precipitate wascollected, rinsed with water, coevaporated with toluene and dried toprovide 5.6 g of solid. A total crude yield of 8.2 g was obtained andthe material was used in subsequent reactions.

EXAMPLE 371-(2-Methoxyethyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0096] 1-(2-Methoxyethyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline 5Noxide (7.67 g; 0.027 mol, Example 36) was dissolved in methylenechloride (100 mL) and cooled to 0-5° C. Cold concentrated ammoniumhydroxide (75 mL) was added with stirring and continued cooling and aprecipitate formed. A solution of p-toluenesulfonyl chloride (5.59 g;0.029 mol) in methylene chloride (20 mL) was slowly added with continuedstirring and cooling. The mixture was maintained at 0-5° C. for about 30minutes after the addition and then stirred at room temperatureovernight. The methylene chloride was evaporated from the mixture andthe solid was filtered from the mixture. The volume of the aqueousfiltrate was reduced under a stream of nitrogen and the resultingprecipitate was collected, rinsed with water and dried to provide 5.1 gof a solid. The solid was taken up in water, acidified with concentratedhydrochloric acid then filtered. The filtrate was made basic with 6Nsodium hydroxide. The resulting precipitate was collected, rinsed withwater and dried to provide colorless needles, m.p. 126-127° C. Analysis:Calculated: C, 62.9; H, 6.3; N, 19.6; Found: C, 62.9; H, 6.05: N, 19.3.

EXAMPLE 38 2-Ethoxymethyl-1-(2-methylpropyl)-1H-imidazo-4,5-c]quinoline

[0097] 4-(2-Methylpropylamino)-3-nitroquinoline (30.5 g; 0.12 mol) wasadded to a mixture of ethyl acetate (800 mL), 5% platinum on carbon (1.5g) and magnesium sulfate (10 g). The mixture was hydrogenated on a Parrapparatus at an initial hydrogen pressure of 30 psi. When thehydrogenation was complete, the solids were removed and the ethylacetate was evaporated. The resulting intermediate diamine was mixedwith ethoxyacetic acid (80.5 mL) and heated with stirring at 130° C. for2-3 hours. The reaction mixture was cooled, poured into 400 mL of waterand then made basic with 6N sodium hydroxide. A green solid wascollected and dried to provide 8.8 g of the desired product. Thestructure was confirmed by nuclear magnetic resonance spectroscopy. Thefiltrate was extracted with ether (4×150 mL). The ether extracts werecombined then evaporated to provide 11.2 g of a green solid. The solidswere combined and used in subsequent reactions.

EXAMPLE 39 2-Ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide

[0098] 2-Ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline(17.4 g; 0.061 mol, Example 38) was dissolved in warm ethyl acetate (150mL) and 32% peracetic acid (14.5 mL) was slowly added to the solution.The mixture was refluxed for 2-3 hours and then cooled to roomtemperature. The precipitate was collected, rinsed with a small amountof ethyl acetate and dried to provide 6.3 g of white solid. Thestructure was confirmed by nuclear magnetic resonance spectroscopy. Thismaterial was used in subsequent reactions.

EXAMPLE 402-Ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0099] 2-Ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5Noxide (6.0 g; 0.02 mol, Example 39) was suspended in methylene chloride(150 mL) and cooled to 0-5° C. Concentrated ammonium hydroxide (60 mL)was cooled to 0-5° C. and added to the suspension. A solution ofp-toluenesulfonyl chloride (4.2 g; 0.022 mol) in methylene chloride (20mL) was slowly added to the mixture with stirring. The mixture wasallowed to stir at room temperature overnight. The methylene chloridewas evaporated and the resulting precipitate was collected and rinsedwith water to give 6.3 g of crude material. The crude material wastriturated with ether. The solid was collected, rinsed with ether anddried to give an analytically pure sample, m.p. 133-137° C. thatanalyzed for half a mole of water. Analysis: Calculated: C, 66.5; H,7.4; N, 18.2; Found: C, 67.0; H, 7.3; N, 18.2.

EXAMPLE 41 4-(3-Methoxypropylamino)-3-nitroquinoline

[0100] 4-Hydroxy-3-nitroquinoline (19.0 g, 0.10 mol) was suspended inmethylene chloride (250 mL). Thionyl chloride (8.0 mL, 0.11 mol) wascombined with dimethylformamide (8.5 mL, 0.11 mol) and slowly added tothe suspension. The resulting mixture was stirred and heated at refluxfor about 2 hours. 3-Methoxypropylamine (10.25 g, 0.115 mol) wascombined with triethylamine (15 mL, 0.20 mol) and slowly added to themixture with stirring. A vigorous heat of reaction was observed. Themixture was evaporated and the residue was suspended in water. Thesuspension was acidified with concentrated hydrochloric acid. A darksolid was collected. The filtrate was made basic with concentratedammonium hydroxide. The precipitate was collected, rinsed with water,and-dried to provide 8.4 g of a yellow solid, m.p. 93-95° C. The darksolid was suspended in 2 liters of water, acidified with concentratedhydrochloric acid, heated on a steam bath for 2-3 hours and thenfiltered while still hot. The filtrate was made basic with concentratedammonium hydroxide. The precipitate was collected, rinsed with water,and dried to provide 9.2 g of a yellow solid, m.p. 93-95° C. Analysis:Calculated: C, 59.8; H, 5.8; N, 16.1; Found: C, 59.6; H, 5.7; N, 16.0.

EXAMPLE 42 2-Ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline

[0101] 4-(3-methoxypropylamino)-3-nitroquinoline (14.6 g; 0.056 mol,Example 41) was added to a mixture of ethyl acetate (1300 mL), 5%platinum on carbon (1.0 g), and magnesium sulfate (5.0 g). The mixturewas hydrogenated on a Parr apparatus at an initial hydrogen pressure of30 psi. When the hydrogenation was complete, the solids were removed andthe ethyl acetate was evaporated. The residual intermediate diamine wasmixed with ethoxyacetic acid (60 mL) and heated at 120° C. for about 8hours. The reaction mixture was cooled to room temperature, poured intowater, made basic with 6N sodium hydroxide and then extracted with ether(5×100 mL). The ether extracts were combined, dried with magnesiumsulfate, then evaporated. The residue was purified by silica gelchromatography (20% methanol in ethyl acetate as eluent) to give 13.3 gof a green oil. This material was used in subsequent reactions.

EXAMPLE 43 2-Ethoxymethyl-1-(3-methoxypropyl-1H-imidazo[4,5-c]quinoline5N Oxide

[0102] 2-Ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinoline(13.3 g; 0.044 mol, Example 42) was dissolved in ethyl acetate (150 mL)and 32% peracetic acid (12 mL) was slowly added to the solution. Thereaction mixture was heated at reflux for 3-4 hours then cooled to roomtemperature. The mixture was evaporated. The residue was diluted withwater (300 mL), made basic with concentrated ammonium hydroxide, thenextracted with ether (7×100 mL). The ether extracts were combined, driedwith magnesium sulfate and evaporated to provide a small amount of ayellow oil. The aqueous base layer was then extracted with ethyl acetate(6×100 mL). The ethyl acetate extracts were combined, washed with brine,dried over magnesium sulfate and evaporated to provide a yellow solid.The solid was coevaporated with toluene to provide 3.56 g of a yellowcrystalline solid. The structure was confirmed by nuclear magneticresonance spectroscopy. The material was used in subsequent reactions.

EXAMPLE 442-Ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0103]2-Ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine 5Noxide (3.5 g; 0.011 mol, Example 43) was dissolved in methylene chloride(25 mL) and cooled to 0-5° C. Concentrated ammonium hydroxide (35 mL)was cooled to 0-5° C. then added to the solution. The resulting mixturewas stirred for about 15 minutes. A solution of p-toluenesulfonylchloride (2.33 g; 0.012 mol) in methylene chloride (10 mL) was slowlyadded with stirring. The reaction mixture was stirred at 0-5° C. for anadditional 30 minutes and then at room temperature overnight. Themethylene chloride was evaporated. The resulting precipitate wascollected, rinsed with water then recrystallized first from ethylacetate and then from dichloroethane to give a crystalline solid, m.p.123.5-125° C. Analysis: Calculated: C, 64.95; H, 7.05: N, 17.8; Found:C, 65.0; H, 7.0; N, 17.7.

EXAMPLE 451-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol

[0104] 3-Amino-4-(2-methylpropylamino)quinoline (43.5 g; 0.20 mol) andformic acid (300 mL) were combined and heated on a steam bath forseveral hours. The reaction mixture was concentrated under vacuum,diluted with water, basified with ammonium hydroxide then extractedtwice with ether. The ether extracts were treated with activatedcharcoal then combined for a total volume of 1200 mL. The volume wasreduced to 500 mL, cooled, then filtered to provide 31.1 g of a lightgreen crystalline solid 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline.

[0105] 1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinoline (4 g; 0.017 mol)was dissolved in tetrahydrofuran (50 mL) then cooled to −78° C. A 7.75mL portion of n-butyl lithium (2.5 M in hexanes) was added dropwise tothe cooled solution. At 15 minutes post addition, benzaldehyde (2.7 mL;0.027 mol) was added and the reaction mixture was allowed to warmslightly. The reaction was quenched with water then diluted with ethylether. The ether was separated, dried with magnesium sulfate thenconcentrated under vacuum. The resulting residue was purified by silicagel chromatography using 5% methanol in methylene chloride as the eluentto give an oily yellow solid. This material was recrystallized frommethylene chloride/hexane to provide a white crystalline solid, m.p.160-166° C. Analysis: Calculated: C, 76.1; H, 6.4; N, 12.7; Found: C,75.9; H, 6.3; N, 12.7.

EXAMPLE 461-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methyl Acetate

[0106] 1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol(3 g; 9 mmol, Example 45) was dissolved in methylene chloride (50 mL)then combined with acetic anhydride (1.3 mL; 13.5 mmol) andtriethylamine (1.6 mL; 11.8 mol) and stirred at room temperatureovernight. The reaction mixture was diluted with methylene chloride,washed sequentially with water and saturated sodium bicarbonatesolution, dried over magnesium sulfate and concentrated under vacuum.The resulting residue was purified by silica gel flash chromatography(50% ethyl acetate in methylene chloride as eluent) to provide a whitesolid. The structure was confirmed by nuclear magnetic resonancespectroscopy.

EXAMPLE 472-(α-Acetoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0107] 1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methylacetate (3 g; 8 mmol, Example 46) was dissolved in ethyl acetate (50 mL)then combined with peracetic acid (2.2 g; 8.8 mmol) and heated at refluxfor about an hour. The reaction mixture was allowed to cool and then wasstirred at room temperature for several days. The resulting precipitatewas collected, rinsed with ethyl acetate and dried to provide 2.6 g of asolid. The structure was confirmed by nuclear magnetic resonancespectroscopy.

EXAMPLE 484-Amino-1-(2-methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol

[0108] 2-(α-acetoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N oxide (2.6 g; 6.7 mmol, Example 47) was dissolved in methylenechloride (40 mL), combined with benzoyl isocyanate (1.2 g; 7.3 mmol) andheated at reflux for about one hour. The reaction mixture was dilutedwith methylene chloride, washed with water, dried over magnesium sulfateand concentrated under vacuum. The residue was taken up in methanol,combined with a catalytic amount of 25% sodium methoxide in methanol,and heated at reflux for several hours. The reaction product waspurified by silica gel chromatography using 2-5% methanol in methylenechloride then recrystallized from ethyl acetate-hexane. Therecrystallized material was co-evaporated twice with methylene chlorideto provide about 0.5 g of a solid, m.p. 125-140° C. Analysis:Calculated: C, 72.8; H, 6.4; N, 16.2; Found: C, 71.9; H, 5.6; N, 15.6.Mass spectrum m/z=347.

EXAMPLE 492-(α-Methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

[0109] 1-(2-Methylpropyl)-α-phenyl-1H-imidazo[4,5-c]quinoline-2-methanol(5.0 g; 15 mmol, Example 45) was dissolved in N,N-dimethylformamide (25mL) then added to a cooled (0-5° C.) suspension of sodium hydride (0.5g; 16.6 mmol) in N,N-dimethylformamide (100 mL). The reaction mixturewas stirred at room temperature for about one hour then combined withmethyl iodide (1.4 mL; 22.6 mmol). Stirring was continued until thereaction was complete as indicated by thin layer chromatography. Thereaction mixture was diluted with ether then quenched with water. Theether layer was separated, washed twice with water, dried over magnesiumsulfate then evaporated under vacuum. The residue was triturated withmethylene chloride/hexane to provide 4.5 g of a solid. The structure wasconfirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 502-(α-Methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5Noxide

[0110] 2-(α-Methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline(4.5 g; 13 mmol, Example 49) was dissolved in ethyl acetate (70 mL),combined with peracetic acid (3.4 g; 14 mmol) and heated at reflux forseveral hours. The reaction mixture was diluted with ethyl acetate,washed with water, dried over magnesium sulfate and concentrated undervacuum. The residue was purified by silica gel chromatography (1-5%methanol in methylene chloride as eluent) to give 3.9 g of an oil whichsolidified on standing. The structure was confirmed by nuclear magneticresonance spectroscopy.

EXAMPLE 512-(α-Methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0111] 2-(α-Methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N oxide (3.9 g; 10.8 mmol, Example 50) was dissolved in methylenechloride (60 mL) then mixed with ammonium hydroxide (20 mL). The mixturewas cooled in an ice bath while a solution of p-toluenesulfonyl chloride(2.2 g; 11.8 mmol) in methylene chloride (20 mL) was added. The reactionmixture was allowed to warm to room temperature and then was stirred forseveral hours. The organic phase was separated, washed with water, driedover magnesium sulfate and concentrated under vacuum. The residue wasrecrystallized from ethyl acetate/hexane to provide 2.5 g of a solid,m.p. 183-184° C. Analysis: Calculated: C, 73.3; H, 6.7; N, 15.5; Found:C, 73.1; H, 6.7; N, 15.3.

EXAMPLE 52α-(4-Chlorophenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0112] Using the method of Example 45,1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2.5 g) was reacted with4-chlorobenzaldehyde to provide 3.1 g of a yellow solid. The structurewas confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 53α-(4-Chlorophenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylAcetate

[0113] Using the method of Example 46,α-(4-chlorophenyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol(2.6 g, 7.1 mmol, Example 52) was reacted with acetic anhydride toprovide the desired product as a thick oil. The structure was confirmedby nuclear magnetic resonance spectroscopy.

EXAMPLE 542-(α-Acetoxy-4-chlorobenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide

[0114] Using the method of Example 47,α-(4-chlorophenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylacetate (2.9 g, 7.1 mmol, Example 53) was oxidized with peracetic acidto provide the 5N oxide as an oil.

EXAMPLE 554-Amino-α-(4-chlorophenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0115] Using the method of Example 48,2-(α-acetoxy-4-chlorobenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N oxide (3.3 g, 7.8 mmol, Example 54) was reacted with benzoylisocyanate and hydrolyzed to provide 0.8 g of the desired product as asolid, m.p. 140-145° C. Analysis: Calculated: C, 66.2; H, 5.6; N, 14.7;Found: C, 65.6; H, 5.5; N, 14.4.

EXAMPLE 56α-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0116] Using the method of Example 45,1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20 g; 89 mmol) wasreacted with valeraldehyde to provide 11.6 g of the desired product as asolid.

EXAMPLE 572-(1-Acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

[0117] Using the general method of Example 46,α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (11.6g; 37 mmol, Example 56) was reacted with acetic anhydride to provide thedesired product.

EXAMPLE 582-(1-Acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0118] Using the general method of Example 47,2-(1-acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (11.5g; 32 mmol, Example 57) was oxidized with peracetic acid to provide thedesired 5N oxide.

EXAMPLE 592-(1-Acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0119] Using the general method of Example 51,2-(1-acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline 5Noxide (12 g; 32 mmol, Example 58) was reacted with tosyl chloride andammonium hydroxide to provide the desired amine.

EXAMPLE 604-Amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanolHemihydrate

[0120] Several drops of 25% sodium methoxide in methanol were added to asolution of2-(1-acetoxypentyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinolin-4-amine(12 g; 32 mmol, Example 59) in methanol and the resulting mixture washeated at reflux for about one hour. The reaction was concentrated undervacuum to provide a solid. A portion of this solid was taken up in alarge volume of methylene chloride, washed with water, dried overmagnesium sulfate and reduced to a volume of about 50 mL. The resultingprecipitate was collected and dried to provide 2.6 g of a whitecrystalline solid, m.p. 208-211° C. Analysis: Calculated: C, 68.0; H,8.1; N, 16.7; Found: C, 67.8; H, 7.7; N, 16.6.

EXAMPLE 612-(1-Methoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0121] Sodium hydride (0.32 g; 10.1 mmol) was added to a suspension of4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol(3 g; 9.2 mmol, Example 60) and the resulting mixture was stirred forabout 2 hours. Methyl iodide (0.82 mL; 13.8 mmol) was added to themixture and stirring was continued overnight. Thin layer chromatographyindicated that the reaction was incomplete so sodium hydride (0.25 g)was added followed two hours later by methyl iodide (1 mL). The reactionwas stirred for several additional hours then quenched with water anddiluted with ethyl acetate. The organic layer was separated, washed withwater, dried over magnesium sulfate and concentrated under vacuum toprovide an oil. The oil was purified by silica gel chromatography (1-3%methanol in methylene chloride as eluent) to provide 0.5 g of a solid,m.p. 125-128° C. Analysis: Calculated: C, 70.55; H, 8.3; % N, 16.5;Found: C, 70.2; H, 8.3; N, 16.0.

EXAMPLE 622-[1-(1-Morpholino)pentyl]-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0122] Thionyl chloride (1 mL; 13.8 mmol) was added to a chilled (0-5°C.) suspension of4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol(3 g; 9.2 mmol, Example 60) in methylene chloride (30 mL). The resultingmixture was stirred for several hours. Morpholine. (8 mL; 90 mmol) wasadded and the reaction mixture was heated at reflux until thin layerchromatography indicated that the reaction was complete. The reactionmixture was diluted with additional methylene chloride, then water andammonium hydroxide were added. The organic layer was separated, washedwith water, dried over magnesium sulfate and concentrated under vacuum.The residue was purified by sequential silica gel chromatography usingethyl acetate as the eluent in the first column and 1-4% methanol inmethylene chloride as the eluent in the second column to give about 1 gof the desired product as a solid m.p. 95-100° C. which analyzes for athird of a mole of water. Analysis: Calculated: C, 68.8, H, 8.45; N,17.4; Found: C, 68.7; H, 8.1; N, 17.4.

EXAMPLE 63α-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol

[0123] Using the general method of Example 45,1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (20 g; 89 mmol) wasreacted with acetaldehyde to provide the desired product. The structurewas confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 642-(1-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

[0124] Using the general method of Example 49,α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (3 g;11 mmol, Example 63) was reacted with methyl iodide to provide 2.4 g ofthe desired product. The structure was confirmed by nuclear magneticresonance spectroscopy.

EXAMPLE 652-(1-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0125] Using the general method of Example 50,2-(1-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (2.4 g;8.5 mmol, Example 64) was oxidized using peracetic acid to provide thedesired 5N oxide.

EXAMPLE 662-(1-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0126] Using the general method of Example 51,2-(1-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline 5Noxide (2.4 g; 8 mmol, Example 65) was aminated to provide 1 g of thedesired product as a crystalline solid, m.p. 185-189° C. which analyzesfor one fourth of a mole of water. Analysis: Calculated: C, 67.4; H,7.5; N, 18.5; Found: C, 67.7; H, 7.4; N, 18.1.

EXAMPLE 67α-Methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methyl Acetate

[0127] Using the general method of Example 46,α-methyl-1-(2-methylpropyl)-1H-imidazo [4,5-c]-quinoline-2-methanol (5.8g, 0.02 mol, Example 16) was reacted with acetic anhydride to providethe desired product.

EXAMPLE 682-(1-Acetoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0128] Using the general method of Example 47α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methylacetate, (6.3 g 0.02 mol, Example 67) was oxidized with peracetic acidto provide the desired 5N oxide as a solid. The structure was confirmedby nuclear magnetic resonance spectroscopy.

EXAMPLE 694-Amino-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylAcetate Hydrate

[0129] Using the general method of Example 51,2-(1-acetoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5Noxide (4.1 g 2.5 mmol, Example 68) was aminated to provide the desiredproduct as a solid, m.p. 152-155° C. which analyzes as containing onefourth of a mole of water. Analysis: Calculated % C 65.3; % H, 6.8; % N,16.9; Found: % C, 65.5; % H, 6.8; % N, 16.9.

EXAMPLE 702-(2-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

[0130] Using the general method of Example 45,2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline (2 g 8.4 mmol,)was reacted with 2-chloroethyl methyl ether (0.76 mL, 10 mmol) toprovide the desired product. The structure was confirmed by nuclearmagnetic resonance spectroscopy.

EXAMPLE 712-(2-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0131] Using the general method of Example 47,2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline (1 g,3.5 mmol, Example 70) was oxidized with peracetic acid to provide 0.75 gof the desired 5N oxide as a yellow solid. The structure was confirmedby nuclear magnetic resonance spectroscopy.

EXAMPLE 722-(2-Methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0132] Using the general method of Example 51,2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5Noxide (0.75 g, Example 71) was aminated to provide 0.4 g of the desiredproduct as a solid, m.p. 168-170° C. Analysis: Calculated: % C, 68.4; %H, 7.4; % N, 18.8; Found: % C, 68.4; % H, 7.4; % N, 18.6.

EXAMPLE 731-[1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-2-one

[0133] 2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (1 g, 4.2mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) then cooled to−78° C. A portion of lithium diisopropyl amide (2.8 mL, 4.2 mmol) wasadded dropwise to the cooled solution. At 10 minutes post addition,N-methoxy-N-methylacetamide (0.45 g, 4.4 mmol), prepared according tothe method of T. A. Oster and T. M. Harris, Tetrahedron Letters, 24,1851 (1983) was added. After 15 minutes the reaction was quenched withwater and the resulting precipitate was collected and dried to providethe desired product as a solid. The structure was confirmed by nuclearmagnetic resonance spectroscopy.

EXAMPLE 74α-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethanol

[0134] 1-[1-(2-Methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]propan-2-one(8 g, 28.4 mmol, Example 73) was suspended in ethanol (400 mL). Sodiumborohydride (1.64 g, 43.3 mmol) was added and the reaction mixture wasstirred at room temperature for about 2 hours. Methanol (about 20 mL)was added and stirring was continued over night. Water was added thenthe solvents were removed under vacuum. The residue was partitionedbetween methylene chloride and water. The methylene chloride layer wasseparated, dried over magnesium sulfate then concentrated under vacuumto give the desired product. The structure was-confirmed by nuclearmagnetic resonance spectroscopy.

EXAMPLE 752-(2-Methoxypropyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline

[0135] α-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethanol(6.5 g, 23 mmol, Example 74) was dissolved in N,N-dimethylformamide (50mL) then cooled to 0° C. Sodium hydride (0.8 g, 25 mmol), 80% dispersionin mineral oil) was added and the resulting mixture was stirred at 0° C.for about 1 hour. Methyl iodide (2.2 mL, 34 mmol) was added and theresulting mixture was stirred at 0° C. for about 1 hour and then allowedto warm to room temperature. The reaction was quenched with water andthen diluted with ethyl acetate. The organic layer was separated, washedseveral times with water, dried over magnesium sulfate then concentratedunder vacuum. The resulting residue was purified by silica gelchromatography using 2-5% methanol in methylene chloride to give about 3g of the desired product. The structure was confirmed by nuclearmagnetic resonance spectroscopy.

EXAMPLE 762-(2-Methoxypropyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0136] Using the general method of Example 47,2-(2-methoxypropyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (3 g,10 mmol, Example 75) was oxidized with peracetic acid to provide 2.1 gof the desired 5N oxide as a solid, m.p. 125-130° C. The structure wasconfirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 772-(2-Methoxypropyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine

[0137] Using the general method of Example 51,2-(2-methoxypropyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline 5Noxide (2 g, 6.4 mmol, Example 76) was aminated to provide 1.3 g of thedesired product as a solid, m.p. 139-141° C. Analysis: Calculated: % C,69.2; % H, 7.7; % N, 17.9; Found: % C, 69.1; % H, 7.8; % N, 17.8.

EXAMPLE 78α-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethyl Acetate

[0138] Using the general method of Example 46,α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-ethanol (9.4g, 33 mmol, Example 74) was reacted with acetic anhydride to provide thedesired product. The structure was confirmed by nuclear magneticresonance spectroscopy.

EXAMPLE 792-(2-Acetoxypropyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline 5NOxide

[0139] Using the general method of Example 47,α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-ethyl acetate(10.7 g, 33 mmol, Example 78) was oxidized with peracetic acid toprovide the desired 5N oxide. The structure was confirmed by nuclearmagnetic resonance spectroscopy.

EXAMPLE 804-Amino-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethylAcetate

[0140] Using the general method of Example 51,2-(2-acetoxypropyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline 5Noxide (10.5 g, 30 mmol, Example 79) was aminated to provide the desiredproduct. The structure was confirmed by nuclear magnetic resonancespectroscopy.

EXAMPLE 814-Amino-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethanol

[0141] Using the general method of Example 60,4-amino-α-methyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-ethylacetate (10.2 g, 30 mmol, Example 80) was hydrolyzed to provide 2 g ofthe desired product as a solid, m.p. 196-197.5° C. Analysis: Calculated:% C, 68.4; % H, 7.4; % N, 18.8; Found: % C, 68.6; % H, 7.5; % N, 18.9.

EXAMPLE 82 7-Chloro-4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline

[0142] Using the general method of Example 41,7-chloro-4-hydroxy-3-nitroquinoline (18 g, 80 mmol,) was chlorinatedusing thionyl chloride. After the chlorination was complete, asindicated by thin layer chromatography, the reaction mixture was allowedto cool to room temperature. Triethylamine (28 mL, 200 mmol) and2-amino-2-methyl-2-propanol (10.3 g, 96 mmol) were added and thereaction mixture was heated at reflux for about 1 hour. The reactionmixture was cooled in an ice bath and the resulting precipitate wascollected and dried to provide the desired product as a solid. Thestructure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 837-Chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0143] Using the general method of Example 42,7-chloro-4-(2-hydroxy-2-methylpropylamino)-3-nitroquinoline (18.5 g, 63mmol, Example 82) was reduced and the resulting diamine reacted withethoxyacetic acid to provide the desired product as a thick, green oil.

EXAMPLE 847-Chloro-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide

[0144] Using the general method of Example 47,7-chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo-[4,5-c]quinoline-1-ethanol(20.9 g, 63 mmol, Example 83) was oxidized with peracetic acid toprovide 14.8 g of the desired oxide as a solid.

EXAMPLE 854-Amino-7-chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0145] Using the general method of Example 51,7-chloro-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl) -1H-imidazo[4,5-c]quinoline 5N oxide (14.8 g, 42 mmol, Example 84) was aminated toprovide 8.6 g of the desired product as a solid, m.p. 238-240° C.Analysis: Calculated: % C, 58.5; % H, 6.1; % N, 16.1; Found: % C, 58.4;% H, 6.0; % N, 16.0.

EXAMPLE 86α,α-Dimethyl-2-hydroxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0146] Using the general method of Example 24,3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline (45 g, 0.19 mol) wasreacted with glycolic acid to provide 35.7 g of the desired product as atan solid. The structure was confirmed by nuclear magnetic resonancespectroscopy.

EXAMPLE 871-(2-Hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methyl Acetate

[0147] Using the general method of Example 2,α,α-dimethyl-2-hydroxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (35.0g, 0.13 mol, Example 86) was reacted with acetyl chloride to provide32.3 goof a tan solid. Nuclear magnetic resonance spectroscopy showedthat the tan solid contained the desired product plus about 10 percentof the diester. The material was used without additional purification.

EXAMPLE 882-Acetoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide

[0148] Using the general method of Example 47,1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methyl acetate(31 g, Example 87) was oxidized with peracetic acid to provide 19.6 g ofcrude 5N oxide.

EXAMPLE 894-Chloro-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylAcetate

[0149] A 16.7 g portion of the crude 5N oxide prepared in Example 88 wassuspended in methylene chloride (1200 mL). Phosphorous oxychloride (3.5mL) was added to the suspension with vigorous stirring over a period ofabout 5 minutes. After about 1.5 hours, the reaction mixture wasfiltered to remove 7.9 g of a solid. The methylene chloride filtrate wascombined with phosphorous oxychloride (1.2 mL) and stirred at roomtemperature for about 20 hours. Saturated sodium bicarbonate solution(250 mL) was added with stirring to the reaction mixture. The layerswere separated. The aqueous layer was extracted with methylene chloride.The methylene chloride layers were combined, dried over magnesiumsulfate and concentrated under vacuum to provide 10.2 g the desiredproduct as a tan solid. The structure was confirmed by nuclear magneticresonance spectroscopy.

EXAMPLE 904-Amino-α,α-dimethyl-2-hydroxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0150] Using the general method of Example 9,4-chloro-1-(2-hydroxy-2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methylacetate (8.3 9, 24 mmol, Example 89) was aminated to provide 2.3 g ofthe desired product as a solid, m.p. 264-271° C. Analysis: Calculated: %C, 62.9; % H, 6.3; % N, 19.6; Found: % C, 62.9; % H, 6.3; % N, 19.3.

EXAMPLE 91 2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinoline

[0151] 3-Amino-4-(phenylmethylamino)quinoline (4 g, 16 mmol) wascombined with ethoxyacetic acid (4.5 mL, 48 mmol) and heated at 120° C.for about 3 hours. The reaction mixture was cooled to room temperature,diluted with water and then made basic with ammonium hydroxide. Theresulting precipitate was collected to provide 5.3 g of the desiredproduct as a solid. The structure was confirmed by nuclear magneticresonance spectroscopy.

EXAMPLE 92 2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinoline 5NOxide

[0152] Using the general method of Example 47,2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline (4.5 g, 14mmol, Example 91) was oxidized with peracetic acid to provide 3.2 g ofthe desired 5N oxide as a solid.

EXAMPLE 932-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0153] Using the general method of Example 51,2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline 5N oxide (3.2g, 9.6 mmol, Example 92) was aminated to provide 1.1 g of the desiredproduct as a solid, m.p. 204-205° C. Analysis: Calculated: % C, 72.3; %H, 6.1; % N, 16.9; Found: % C, 72.1; % H, 5.7; % N, 16.6.

EXAMPLE 94 α,α-Dimethyl-2-methoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0154] 3-Amino-4-(2-hydroxy-2-methylpropylamino)quinoline (7.5 g, 32mmol) was combined with methoxyacetic acid (7.5 mL, 97 mmol) and heatedat about 170° C. for about 3 hours. The resulting solid residue wasdissolved in ethyl acetate (150 mL). The ethyl acetate solution wasextracted twice with 0.2 N sodium hydroxide, washed with water, driedover magnesium sulfate, treated with activated charcoal and thenconcentrated to a volume of about 50 mL. Hexane was added to the ethylacetate and the resulting precipitate was collected and dried to provide0.9 g of the desired product as a crystalline solid, m.p. 145-148° C.Analysis: Calculated: % C, 67.3; % H, 6.7; % N, 14.7; Found: % C, 67.2;% H, 6.6; % N, 14.6.

EXAMPLE 951-(2-Hydroxy-2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline5N Oxide

[0155] Using the general method of Example 47,α,α-dimethyl-2-methoxymethyl-1H-imidazo [4,5-c]-quinoline-1-ethanol (6.6g, 23 mmol, Example 94) was oxidized with peracetic acid to provide 5.7g of the desired 5N oxide. A small sample was recrystallized from ethylacetate to provide an analytical sample, m.p. 175-197° C. Analysis:Calculated: % C, 63.8; % H, 6.4; % N, 14.0; Found: % C, 63.8; % H, 6.4;% N, 13.8.

EXAMPLE 964-Amino-α,α-dimethyl-2-methoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0156] Using the general method of Example 51,1-(2-hydroxy-2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline5N oxide (4.7 g, 16 mmol, Example 95) was aminated to provide 2.4 g ofthe desired product as a solid, m.p. 204-207° C. Analysis: Calculated: %C, 64.0; % H, 6.7; % N, 18.6; Found: % C, 64.1; % H, 6.8; % N, 18.6.

EXAMPLE 97α,α-Dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0157] Using the general method of Example 91,3-amino-4-(2-hydroxy-2-methylpropylamino)quinoline (46.2 g. 0.20 mol)was reacted with ethoxyacetic acid (62.5 g, 0.6 mol) to provide 53.6 gof crude product as a greyish solid. A small amount was recrystallizedfrom toluene to provide 3.6 g of a colorless solid, m.p. 117-120° C.Analysis: Calculated: % C 68.2; % H, 7.1; % N, 14.0; Found: % C, 68.5; %H, 7.1; % N, 14.0.

EXAMPLE 982-Ethoxymethyl-1-(2-Hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N Oxide

[0158] Using the general method of Example 47α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol (59.9g, 0.2 mol, Example 97) was oxidized with peracetic acid to provide 59.9g of crude 5N oxide as a solid.

EXAMPLE 994-Amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0159] Using the general method of Example 51,2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinoline5N oxide (30.0 g, 0.095 mol, Example 98) was aminated to provide 25.7 gof crude product as an off white solid. A portion (20.3 g) of the crudeproduct was suspended in methanol (125 mL) and methylene chloride (60mL) was added to the suspension. The resulting solution was treated withcharcoal then filtered. The filtrate was evaporated under heat to removethe methylene chloride and reduce the total volume to about 110 mL. Thesolution was then allowed to cool to room temperature. The resultingprecipitate was collected, rinsed with methanol and dried to provide12.1 g of the desired product as a colorless crystalline solid, m.p.190-193° C. Analysis: Calculated: % C, 65.0; % H, 7.1; % N, 17.8; Found:% C, 64.8; % H, 7.1; % N, 17.9.

EXAMPLE 1004-Chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0160] 3-Amino-2-chloro-4-(2-hydroxy-2-methylpropylamino)quinoline (2.0g, 7.5 mmol) was combined with acetonitrile (80 mL). Ethoxyacetylchloride (0.92 g, 7.5 mmol) was added to the reaction mixture. Afterabout 5 minutes a yellow precipitate formed. p-Toluenesulfonic acid (0.1g) was added and the reaction mixture was heated to reflux. Refluxingwas continued for about 120 hours at which time the reaction mixture washomogeneous. The reaction mixture was cooled and the acetonitrile wasremoved under vacuum. The resulting residue was dissolved in methylenechloride and washed with dilute ammonium hydroxide. The aqueous phasewas extracted with methylene chloride (3×25 mL). The organic phases werecombined, dried over magnesium sulfate and then concentrated to provide2.6 g of crude product as a dark yellow solid. The crude product wasrecrystallized from t-butylmethyl ether to provide 1.8 g of a solid. Thestructure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 1014-Amino-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0161]4-Chloro-α,α-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol(1.0 g, 3 mmol, Example 100) and 7% methanolic ammonia (30 mL) wereplaced in a steel pressure vessel at about 150-160° C. for 6 hours. Thevessel was cooled to below room temperature and the reaction solutionremoved and treated with methanolic potassium hydroxide. The solutionwas then evaporated to a low volume and diluted with water. Theresulting precipitate was collected, washed with water and dried toprovide 0.7 g of the crude product as a solid. The crude product wasrecrystallized from a mixture of ethyl acetate and methanol to provide acolorless solid.

EXAMPLE 102 2-Methoxymethyl-1-phenylmethyl-1H-imidazo[4, 5-c]quinoline

[0162] Using the general method of Example 91,3-amino-4-(phenylmethylamino)quinoline (4.0 g, 16 mmol) was reacted withmethoxyacetic acid (3.7 mL) to provide 4.4 g of the desired product as asolid. The structure was confirmed by nuclear magnetic resonancespectroscopy.

EXAMPLE 103 2-Methoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinoline 5NOxide

[0163] Using the general method of Example 47,2-methoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline (4.4 g, 14.5mmol, Example 102) was oxidized with peracetic acid to provide 3 g ofthe desired 5N oxide as a solid.

EXAMPLE 1042-Methoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0164] Using the general method of Example 51,2-methoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinoline 5N oxide (3g, 9 mmol, Example 103) was aminated to provide 2.0 g of the desiredproduct as a solid, m.p. 202-204° C. Analysis: Calculated: % C, 71.7; %H, 5.7; % N, 17.6; Found: % C, 71.4; % H, 5.7; % N, 17.4.

EXAMPLE 105 4-(3-Methylbutylamino)-3-nitroquinoline

[0165] Using the general method of Example 41,4-hydroxy-3-nitroquinoline (19 g, 0.10 mole) was chlorinated and thenreacted with isoamylamine (10.5 g, 0.12 mole) to provide the crudeproduct as a yellow solid. This solid was recrystallized from hexane toprovide the desired product as a solid, m.p. 99-100° C. Analysis:Calculated: % C, 64.8; % H, 6.6; % N, 16.2; Found: % C, 64.8; % H, 6.6;% N, 16.1.

EXAMPLE 106 3-Amino-4-(3-methylbutylamino)quinoline

[0166] 4-(3-Methylbutylamino)-3-nitroquinoline (10 g, 0.04 mole; Example105) was combined with toluene (300 mL), 5% palladium on carbon (1 g)and magnesium sulfate. The mixture was hydrogenated on a Parr apparatusat an initial pressure of 47 psi (3.3 Kg/cm²). When the hydrogenationwas complete, the solids were removed by filtration and the filtrate wasevaporated to provide the diamine. A sample (1.5 g) was recrystallizedfrom hexane to provide the desired product as a solid, m.p. 92-94° C.Analysis: Calculated: % C, 73.3; % H, 8.4; % N, 18.3; Found: % C, 73.0;% H, 8.3; % N, 18.3.

EXAMPLE 107 2-Ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinoline

[0167] 3-Amino-4-(3-methylbutylamino)quinoline (7 g, 0.03 mole; Example106) was combined with ethoxyacetic acid (8 mL, 0.08 mole) and heated at150-160° C. for about 2 hours. The reaction mixture was cooled to roomtemperature, diluted with water (100 mL), made basic with sodiumhydroxide and then extracted with ethyl acetate. The extract was driedover magnesium sulfate then evaporated to provide the crude product as acrystalline solid. The solid was recrystallized from hexane to providethe desired product as a solid, m.p. 64-65° C. Analysis: Calculated: %C, 72.7; % H, 7.8; % N, 14.1; Found: % C, 72.5; % H, 7.7; % N, 14.1.

EXAMPLE 108 2-Ethoxymethyl-1-(3-methylbutyl)-1H-imidaz[4,5-c]quinoline5N Oxide

[0168] 2-Ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinoline (6 g,0.02 mole, Example 107) was dissolved in methyl acetate (60 mL) thencombined with peracetic acid (8.4 g, 0.04 mole) and heated until thereaction was complete as determined by thin layer chromatography (silicagel, ethyl acetate). The reaction mixture was evaporated. The residuewas azeotroped 5 times with heptane (250 mL) to provide the desired 5Noxide.

EXAMPLE 1092-Ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amineHydrochloride

[0169] Using the general method of Example 51,2-ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinoline 5N oxide (6g, 0.02 mole, Example-108) was aminated to provide the desired productas a solid, m.p. 291-292° C. Analysis: Calculated: % C, 62.0; % H, 7.2;% N, 16.0; Found: % C, 62.0; % H, 7.1; % N, 16.0.

EXAMPLE 110N-[2-Chloro-4-(2-hydroxy-2-methylpropyl)amino-3-quinolinyl]-3-methoxypropanamide

[0170] 3-Methoxypropionyl chloride (5.5 g, 0.045 mole) was slowly addedwith stirring to a solution of1[(3-amino-2-chloro-4-quinolinyl)amino]-2-methyl-2-propanol (10 g, 0.038mole) in acetonitrile (140 mL). After the addition was completed, thereaction mixture was heated at reflux for 30 minutes then allowed tostir at room temperature overnight. The reaction mixture was filtered toprovide 12.4 g of the desired product as a solid.

EXAMPLE 1114-Amino-α,α-dimethyl-2-methoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0171]N-[2-Chloro-4-(2-hydroxy-2-methylpropyl)amino-3-quinolinyl]-3-methoxypropanamide(6 g, Example 110) was added to 5% ammonia in methanol (60 mL). Themixture was heated in a Parr bomb for 5 hours at approximately 150° C.The solvent was evaporated under vacuum to give a brown residue. Theresidue was diluted with water and sodium bicarbonate then extractedwith ethyl acetate. The ethyl acetate extract was washed with water,dried over magnesium sulfate then evaporated to provide a tan solid. Thesolid was purified by silica gel chromatography to provide 1.64 g of thedesired product as a solid, m.p. 174-175° C. Analysis: Calculated: % C,65.0; % H, 7.0; % N, 17.8; Found: % C, 64.8; % H, 7.0; % N, 17.7.

EXAMPLE 112 3-Butylamino-2-chloro-3-nitroquinoline

[0172] Triethylamine (37.8 g, 0.37 mole) was added with stirring to asuspension of 4-hydroxy-3-nitro-2(1H)-quinolinone (50 g, 0.24 mole) intoluene (175 mL) while maintaining the temperature of the reactionmixture below 40° C. After the addition was complete, the reactionmixture was cooled to 15° C. and phosphorous oxychloride (152 g, 0.99mole) was added while maintaining the temperature of the reactionmixture below 55° C. After the addition was complete, the reactionmixture was refluxed at 110° C. until the reaction was complete asdetermined by thin layer chromatography (silica gel; 50:50 ethylacetate:hexanes). The reaction mixture was allowed to cool to roomtemperature and was then poured into a mixture of ice and water (400mL). The mixture was stirred for 1 hour. The phases were separated andthe aqueous phase was extracted twice with toluene. The toluene extractswere combined with the organic phase, washed with water, filtered toremove a small amount of solid then dried over magnesium sulfate to givea solution of the dichloro intermediate in toluene. This solution wascombined with triethylamine (25.5 g, 0.25 mole) then stirred for 15minutes. n-Butylamine (21.3 g, 0.29 mole) was added and the reactionmixture was heated at 50° C. for 90 minutes. The reaction mixture wasallowed to cool to room temperature, combined with concentratedhydrochloric acid (71 mL) then stirred at room temperature for 1 hour.The resulting solid was collected by filtration, rinsed with acetonethen slurried with acetone to provide the hydrochloride salt of thedesired product as a yellow solid. The solid was added to a cooledsolution of sodium hydroxide (40 g) in water (200 mL) and stirred for 1hour. The solid was collected by filtration, rinsed with water and driedat 45° C. under vacuum to provide 34 g of the desired product. A 1 gportion was recrystallized from toluene to provide a sample foranalysis. Analysis: Calculated: % C, 55.8; % H, 5.0; % N, 15.0; Found: %C, 55.6; % H, 5.0; % N, 14.9.

EXAMPLE 113 3-Amino-4-butylamino-2-chloroquinoline

[0173] 4-Butylamino-2-chloro-3-nitroquinoline (33 g, 0.12 mole, Example112) was combined with toluene (200 mL) and 5% platinum on carbon (1 g).The mixture was hydrogenated on a Parr apparatus at an initial pressureof 38 psi (2.7 Kg/cm²). When the hydrogenation was complete, thecatalyst was removed by filtration and the filtrate was concentrated toprovide a brown liquid. The liquid was chilled in an ice bath to providean orange solid. The solid was collected by filtration, slurried withdiethyl ether for 30 minutes then filtered to provide 20 g of thedesired product as a tan solid. The structure was confirmed by nuclearmagnetic resonance spectroscopy.

EXAMPLE 114 N-(4-Butylamino-2-chloro-3-quinolinyl)-3-methoxypropanamide

[0174] Using the general method of Example 110,3-amino-4-butylamino-2-chloroquinoline (10 g, 0.04 mole, Example 113)was reacted with 3-methoxypropionyl chloride to provide 10.3 g of thedesired product as a yellow solid.

EXAMPLE 115 1-Butyl-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0175] Using the general method of Example 111,N-(4-butylamino-2-chloro-3-quinolinyl)-3-methoxypropanamide (10 g, 0.027mole, Example 114) was cyclized and aminated to provide the desiredproduct as a solid, m.p. 149-151° C. Analysis: Calculated: % C, 68.4; %H, 7.4; % N, 18.8; Found: % C, 68.5; % H, 7.3; % N, 18.7.

EXAMPLE 116 N-(4-Butylamino-2-chloro-3-quinolinyl)ethoxyacetamide

[0176] Using the general method of Example 110,3-amino-4-butylamino-2-chloroquinoline (10 g, 0.04 mole, Example 113)was reacted with ethoxyacetyl chloride to provide 9.8 g of the desiredproduct as a yellow solid.

EXAMPLE 117 1-Butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine

[0177] Using the general method of Example 111,N-(4-butylamino-2-chloro-3-quinolinyl)ethoxyacetamide (9 g, 0.024 mole,Example 116) was cyclized and aminated to provide 1.9 g of the desiredproduct as a solid, m.p. 139-140° C. Analysis: Calculated: % C, 68.4; %H, 7.4; % N, 18.8; Found: % C, 68.6; % H, 7.3; % N, 18.9.

EXAMPLE 1184-[(2-Chloro-3-nitro-4-quinolinyl)amino]-3-methyl-1-butene-3-ol

[0178] Triethyl amine (6.2 mL, 0.045 mole) was added to a solution of2,4-dichloro-3-nitroquinoline (10.9 g, 0.045 mole) in methylene chloride(60 mL). 4-Amino-3-methyl-1-butene-3-ol was added and the reactionmixture was heated at reflux for several hours before being concentratedunder vacuum. The residue was chilled in an ice bath to give a solid.The solid was recrystallized from toluene to provide 17.1 g of thedesired product as a yellow solid. The structure was confirmed bynuclear magnetic resonance spectroscopy.

EXAMPLE 1191-[(3-Amino-2-chloro-4-quinolinyl)amino]-α-ethyl-α-methylethanol

[0179] 4-[(2-Chloro-3-nitro-4-quinolinyl)amino]-3-methyl-1-butene-3-ol(10.8 g, 0.035 mole, Example 118) was combined with ethanol (300 mL) and0.5 g 5% platinum on carbon. The mixture was hydrogenated on a Parrapparatus. The reaction mixture was filtered through celite and thefiltrate was concentrated to provide an oil. The oil was purified bysilica gel column chromatography. An attempt to crystallize the purifiedoil using ethanol and water produced an oil. The mixture wasconcentrated under vacuum with toluene then extracted with methylenechloride. The methylene chloride extract was dried over magnesiumsulfate then concentrated under vacuum to provide 6.6 g of the desiredproduct as a solid, m.p. 99-101° C. Analysis: Calculated: % C, 60.1; %H, 6.5; % N, 15.0; Found: % C, 60.0; % H, 6.4; % N, 14.8.

EXAMPLE 120N-[2-Chloro-4-(2-hydroxy-2-methylbutyl)amino-3-quinolinyl]ethoxyacetamide

[0180] Ethoxyacetyl chloride (0.93 g, 7.6 mmole) was added to a solutionof 1-[(3-amino-2-chloro-4-quinolinyl)amino]-α-ethyl-α-methylethanol (2g, 7.2 mmole, Example 119) in methylene chloride (10 mL). The reactionmixture was heated at reflux for 30 minutes, cooled to room temperature,diluted with methylene chloride, extracted 3 times with aqueous sodiumbicarbonate, dried over magnesium sulfate and then concentrated undervacuum to provide a liquid which solidified on standing. The solid wasslurried with a mixture of toluene and hexane then isolated byfiltration to provide 2.2 g of the desired product as a solid. Thestructure was confirmed by nuclear magnetic resonance spectroscopy.

EXAMPLE 1214-Amino-2-ethoxymethyl-α-ethyl-α-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol

[0181] Using the general method of Example 111,N-[2-chloro-4-(2-hydroxy-2-methylbutyl)-amino-3-quinolinyl]ethoxyacetamide(2.1 g, 5.7 mmole, Example 120) was cyclized and aminated to provide 0.7g of the desired product as a solid, m.p. 189-191° C. Analysis:Calculated: % C, 65.8; % H, 7.4; % N, 17.1; Found: % C, 65.1; % H, 7.2;% N, 16.8.

EXAMPLE 122 N-Butyl-3-nitro-4-quinolinamine

[0182] Using the general method of Example 41,4-hydroxy-3-nitroquinoline (38.4 g, 0.2 moles) was chlorinated thenreacted with n-butylamine (24.7 mL, 0.4 mole) to provide the desiredproduct as a yellow sold.

EXAMPLE 123 1-Butyl-1H-imidazo[4,5-c]quinoline-2-methanol

[0183] Using the general method of Example 1,N-butyl-3-nitro-4-quinolinamine (9.8 g, 0.04 mole, Example 122) washydrogenated then reacted with glycolic acid (9.1 g, 0.12 mole) toprovide 8.0 g of the desired product as a solid. A small sample wasrecrystallized from ethyl acetate to provide pure material, m.p.146-149° C. Analysis: Calculated: % C, 70.6; % H, 6.7; % N, 16.5; Found:% C, 70.3; % H, 6.7; % N, 16.3.

EXAMPLE 124 1-Butyl-1H-imidazo[4,5-c]puinoline-2-methyl Acetate

[0184] Using the general method of Example 46,1-butyl-1H-imidazo[4,5-]quinoline-2-methanol (7.5 g, 0.029 mole, Example123) was reacted with acetic anhydride to provide 8.2 g of the desiredproduct as a solid. A small sample was recrystallized from ethyl acetateto provide a pure sample, m.p. 154-157° C. Analysis: Calculated: % C,68.7; % H, 6.4; % N, 14.1; Found: % C, 68.8; % H, 6.4; % N, 14.2.

EXAMPLE 125 1-Butyl-1H-imidazo[4,5-c]quinoline-2-methyl Acetate 5N OxideMonohydrate

[0185] Using the general method of Example 108,1-butyl-1H-imidazo[4,5-c]quinoline-2-methyl acetate (7.8 g, 0.026 mole,Example 124) was oxidized to provide 6.2 g of the crude 5N oxide assolid. A small sample was recrystallized from isopropanol to providepure material, m.p. 184-187° C. Analysis: Calculated: % C, 61.6; % H,6.4; % N, 12.7; Found: % C, 61.8; % H, 6.2; % N, 12.6.

EXAMPLE 126 1-Butyl-4-chloro-1H-imidazo[4,5-c]-quinoline-2-methylAcetate

[0186] Using the general method of Example 6,1-butyl-1H-imidazo[4,5-c]quinoline-2-methyl acetate 5N oxide monohydrate(6.0 g, 0.019 mole, Example 125) was chlorinated to provide a solid. Thesolid was purified by column chromatography (silica gel; ethyl acetate)to provide 3.7 g of the desired product as a solid. A 0.5 g portion wasrecrystallized from toluene to provide pure material, m.p. 169-171° C.Analysis: Calculated: % C, 61.5; % H, 5.5; % N, 12.7; Found: % C, 61.4;% H, 5.4; % N, 12.5.

EXAMPLE 127 1-Butyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-methanol

[0187] 1-Butyl-4-chloro-1H-imidazo[4,5-c]quinoline-2-methyl acetate (3.1g, 9.3 mmole, Example 126) was stirred overnight in 30 mL of 12% ammoniain methanol. The reaction mixture was concentrated under vacuum and theresidue was slurried with water for about 30 minutes. The solid wascollected by filtration and dried with toluene using a Dean-Stark trapto provide 2.2 g of the desired product, m.p. 184-185° C. Analysis:Calculated: % C, 62.2; % H, 5.6; % N, 14.5; Found: % C, 62.0; % H, 5.5;% N, 14.3.

EXAMPLE 128 4-Amino-1-butyl-1H-imidazo[4,5-c]quinoline-2-methanol

[0188] 1-Butyl-4-chloro--1H-imidazo[4,5-c]quinoline-2-methanol (2 g, 6.9mmole, Example 127) was combined with 12 mL of 12% ammonia in methanoland heated in a Parr bomb at 160° C. for about 20 hours. The resultingsolid was collected, rinsed with methanol then purified by silica gelchromatography using ethyl acetate/methanol as the eluent. The resultingsolid was slurried with ethyl acetate, collected by filtration and driedto provide the desired product, m.p. 223-225° C.

Antiviral Activity and Interferon Induction in Guinea Pigs

[0189] The test methods described below demonstrate the ability ofcompounds of the invention to reduce the number and severity of lesionsdeveloped by guinea pigs infected with Type II Herpes simplex virus andto induce the biosynthesis of interferon in guinea pigs.

[0190] Female Hartley guinea pigs weighing 200 to 250 g are anesthetizedwith methoxyflurane (available under the tradename METAFANE™ fromPitman-Moore, Inc., Washington Crossing, N.J.), after which the vaginalarea is swabbed with a dry cotton swab. The guinea pigs are theninfected intravaginally with a cotton swab saturated with Herpes simplexvirus Type II strain 333 (1×10⁵ plaque forming units/mL). Guinea pigsare assigned to groups of 7 animals; one group for each treatment andone to serve as a control (vehicle treated). The compounds of theinvention are formulated in water containing 5% Tween 80 (apolyoxyethylene sorbitan monooleate available from Aldrich ChemicalCompany, Inc., Milwaukee, Wis.). The guinea pigs are treated orally oncedaily for four consecutive days starting 24 hours after infection.

[0191] Antiviral Activity

[0192] Antiviral activity is evaluated by comparing lesion developmentin compound-treated versus vehicle-treated guinea pigs. External lesionsare scored 4, 7, 8 and 9 days after infection using the following scale:0—no lesion, 1—redness and swelling, 2—a few small vesicles, 3—severallarge vesicles, 4—large ulcers with necrosis and 5—paralysis. Themaximum lesion score of each guinea pig is used to calculate thepercentage lesion inhibition. The percentage lesion inhibition iscalculated as follows:$100 - \left( \frac{\sum\quad {{maximum}\quad {lesion}\quad {scores}\quad {of}\quad {treatment}\quad {group} \times 100}}{\sum\quad {{maximum}\quad {lesoion}\quad {scores}\quad {of}\quad {control}\quad {group}}} \right)$

[0193] Interferon Induction

[0194] Twenty-four hours after the initial dose of test compound hasbeen administered, blood is obtained from 3 guinea pigs from eachtreatment group by cardiac puncture of methoxyflurane anesthetizedanimals. Blood is pooled and allowed to clot at room temperature. Afterlow speed centrifugation, serum is collected and stored at −70° C. untilanalysis.

[0195] Interferon levels in the guinea pig serum are determined in astandard microtiter assay using transformed guinea pig cells (ATCC CRL1405). The interferon assay is done in 96 well microtiter plates.Confluent monolayers of transformed guinea pig cells are treated withdilutions of guinea pig serum made with medium 199 (GIBCO, Grand Island,NY). The cell and serum dilutions are incubated at 37° C. overnight. Thefollowing day, the medium and serum are removed and about 10 plaqueforming units of Mengovirus are added to each well. Controls consist ofwells that receive no guinea pig serum (virus positive control) andwells that. receive no virus (virus negative control). Cells and virusare incubated for 2 to 3 days at 37° C. before quantifying for viralcytopathic effect. The viral cytopathic effect is quantified by stainingwith 0.05% crystal violet followed by spectrophotometric absorbancemeasurements. The titer of interferon in serum is expressed as units/mLand is the reciprocal of the highest dilution that protects cells fromvirus.

[0196] Results are shown in the table below. Antiviral Activity andInterferon Induction in Guinea Pigs Compound of Dose % Lesion ReferenceExample mg/kg Inhibition Units/mL  9 2  37%     266 10 0.5  29% not run11 1 100% >12,800 11 0.5 100% >12,800 11 0.1  50% not run 12 2100% >12,800 12 0.5  82% >12,800 13 2  67% not run 20 2 100% not run

[0197] These results show that the tested compounds of the inventioninhibit Herpes simplex virus type II lesions in guinea pigs. Thosecompounds tested were also shown to induce interferon biosynthesis inguinea pigs.

Interferon-α Induction in Human Cells

[0198] The test methods described below demonstrate the ability ofcompounds of the invention to induce the biosynthesis of interferon-α inhuman cells.

[0199] An in vitro human blood cell system was used to assessinterferon-α induction by compounds of the invention. Activity is basedon the measurement of interferon secreted into culture medium.Interferon is measured by bioassay.

[0200] Blood Cell Preparation for Culture

[0201] Whole blood is collected by venipuncture into EDTA vacutainertubes. Peripheral blood mononuclear cells (PBM) are prepared byLeucoPREP™ Brand Cell Separation Tubes (available from Becton Dickinson)and cultured in RPMI 1640 medium (available from GIBCO, Grand Island,N.Y.) containing 25 mM HEPES4-(2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid and L-glutamine (1%penicillin-streptomycin solution added) with 10% autologous serum added.Alternatively, whole blood diluted 1:10 with RPMI 1640 mediumsupplemented with 25 mM HEPES and L-glutamine with 1%penicillin-streptomycin solution added can be used. 200 μL portions ofdiluted whole blood or of PBM in medium are added to 96 well (flatbottom) MicroTest™ III tissue culture plates.

[0202] Compound Preparation

[0203] The compounds are solubilized in water, ethanol, or dimethylsulfoxide then diluted with distilled water, 0.01N sodium hydroxide or0.01N hydrochloric acid. (The choice of solvent will depend on thechemical characteristics of the compound being tested.) Compounds areinitially tested in a concentration range of from about 0.1 μg/mL toabout 5 μg/mL. Compounds that show induction at a concentration of 0.5μg/mL are then tested in a concentration range of 0.01 μg/mL to 5.0μg/mL.

[0204] Incubation

[0205] The solution of test compound is added (in a volume less than orequal to 50 μL) to the wells containing 200 μL of PBM in medium ordiluted whole blood. Solvent and/or medium is added to control wells(i.e., wells with no test compound) and also as needed to adjust thefinal volume of each well to 250 μL. The plates are covered with plasticlids, vortexed gently and then incubated for 24 hours at 37° C. with a5% carbon dioxide atmosphere.

[0206] Separation

[0207] Following incubation, the plates are covered with PARAFIL™ andthen centrifuged at 1000 rpm for 15 minutes at 4° C. in a Damon IECModel CRU-5000 centrifuge. Medium (about 175 μL) is removed from 4 to 8wells and pooled into 2 mL sterile freezing vials. Samples aremaintained at −70° C. until analysis.

[0208] Interferon Analysis/Calculation

[0209] Interferon is determined by bioassay using A549 human lungcarcinoma cells challenged with encephalomyocarditis. The details of thebioassay method are described by G. L. Brennan and L. H. Kronenberg in“Automated Bioassay of Interferons in Micro-test Plates”, Biotechniques,June/July; 78, 1983., incorporated herein by reference. Briefly statedthe method is as follows: interferon dilutions and A549 cells areincubated at 37° C. for 12 to 24 hours. The incubated cells are infectedwith an inoculum of encephalomyocarditis virus. The infected cells areincubated for an additional period at 37° C. before quantifying forviral cytopathic effect. The viral cytopathic effect is quantified bystaining followed by spectrophotometric absorbance measurements. Resultsare expressed as a interferon reference units/mL based on the valueobtained for NIH HU IF-L standard. The interferon was identified asessentially all interferon alpha by testing in checkerboardneutralization assays against rabbit anti-human interferon (beta) andgoat anti-human interferon (alpha) using A549 cell monolayers challengedwith encephalomyocarditis virus. Results are shown in the table belowwherein the absence of an entry indicates that the compound was nottested at the particular dose concentration. Results designated as “<” acertain number indicate that interferon was not detectable in amountsabove the lower sensitivity level of the assay. Interferon-_Induction inHuman Cells Com- pound _Reference Units/mL of Dose Concentration (μg/mL)Example 0.01 0.05 0.10 0.50 1.0 5.0 Cell Type 9 <1.8 16 140 750 750 750PBM 10 — — <1.5 96 120 120 whole blood 10 <1.3 28 140 750 750 190 PBM 11— — 330 330 250 140 whole blood 11 330 330 570 570 570 570 PBM 12 — —<1.8 37 140 330 whole blood 13 — — <1.9 10 10 4 PBM 15 — — <1.8 250 430750 PBM 20 — — 85 440 250 190 whole blood 20 <1.8 190 190 1000 1000 1000PBM 23 — — <1.8 <1.8 84 250 whole blood 27 <4 24 3300 550 370 490 PBM 29— — <5.4 440 1000 580 PBM 30 — — <4 <4 <4 72 PBM 31 <4 18 2500 370 280370 PBM 34 <4 <4 1600 550 180 200 PBM 37 — — <4 2500 2500 210 PBM 40 — —680 230 210 210 PBM 44 — — 3000 430 430 760 PBM 48 — — 3100 840 330 1300PBM 51 — — <5 <5 1000 330 PBM 55 — — <4 1500 1500 490 PBM 60 — — 1700430 570 570 PBM 61 — — 64 1300 330 330 PBM 62 — — <5 <5 31 760 PBM 66 —— <5 <5 1000 1000 PBM 69 <6.4 <6.4 1000 680 390 900 PBM 72 — — 200 210220 420 PBM 77 <6.3 <6.3 2600 390 250 280 PBM 81 — — 1100 2200 460 1100PBM 85 — — 86 100 220 230 PBM 90 <6.4 640 3000 640 420 580 PBM 93 — —850 280 300 300 PBM 96 <6.4 44 1200 460 1000 900 PBM 99 28 316 280 790790 630 PBM 104 <2.7 <2.7 310 180 140 310 PBM 109 <1.4 1000 1000 97 8378 PBM 111 190 65 65 49 55 61 PBM 115 91 96 120 190 190 240 PBM 117 <4.4360 340 140 91 110 PBM

[0210] These results show that the tested compounds of the inventioninduce interferon biosynthesis at detectable levels in human whole bloodand/or PBM cells over a wide range of dose concentrations.

Interferon Induction in Mice

[0211] The test methods described below demonstrate the ability ofcompounds of the invention to induce interferon biosynthesis in mice.

[0212] For each dose level being tested, three groups (three mice pergroup) of CFW male mice (nonfasted; weighing 23-28 g) are dosed orallywith compound. One hour later blood samples are withdrawn from the firstgroup. The samples are pooled then centrifuged. The serum is removedfrom the centrifuge tube, split into two portions, then placed infreezing vials and maintained at −70° C. until analysis. This procedureis repeated at 2 hours with the second group of mice and at 4 hours withthe third group of mice.

[0213] Interferon Analysis/Calculation

[0214] Samples are assayed as described above in connection with theanalysis of interferon induction in human cells. The results areexpressed in the table below as α/β reference units/mL based on thevalue obtained for a mouse MU-1-IF standard. Results are shown in thetable below wherein results designated as “<” a certain number indicatethat interferon was not detectable in amounts above the lowersensitivity level of the assay. Interferon Induction in Mice ReferenceUnits/mL Compound of Example Dose mg/kg 1 hr 2 hr 4 hr 9 30 2900 5000 49 10 330 740 ≦47 9 3 ≦47 ≦47 <47 9 1 <47 <47 <47 10 10 <120 <120 600 103 <120 <120 <120 10 1 <120 <120 <120 10 0.3 <120 <120 <120 11 30 8502500 40 11 10 1100 2500 280 11 3 490 1900 30 11 1 280 1100 71 12 30 8505800 40 12 10 850 850 40 12 3 54 40 <18 12 1 94 160 <18 13 10 700 1200400 13 3 230 400 130 13 1 130 530 ≦100 13 0.3 <59 ≦130 <59 15 10 2703100 270 15 3 <120 270 <120 15 1 <120 <120 <120 15 0.3 <120 <120 <120 2030 2200 8700 320 20 10 2200 5000 100 20 3 970 1200 140 20 1 140 560 <4723 30 1200 1200 140 27 10 130 690 <45 27 3 <59 230 <45 27 1 <45 <45 <4527 0.3 <45 <45 <45 29 10 <45 <45 <45 29 3 <45 <45 <45 29 1 <45 <45 <4529 0.3 <45 <45 <45 30 10 <120 600 <120 30 3 <120 <120 <120 30 1 <120<120 <120 30 0.3 <120 <120 <120 31 10 960 5000 550 31 3 420 420 320 31 1<61 140 ≦61 31 0.3 <61 <61 <61 34 10 1100 1100 180 34 3 420 420 140 34 1140 320 ≦61 34 0.3 ≦61 ≦61 ≦61 37 10 270 ≦270 ≦270 37 3 <120 <120 <12037 1 <120 <120 <120 37 0.3 <120 <120 <120 60 10 870 3400 1100 60 3 380870 290 60 1 290 1500 120 60 0.3 120 870 ≦56 61 10 290 1100 160 61 3 290500 120 61 1 120 220 97 61 0.3 <56 <56 <56 62 10 380 1100 380 62 3 220870 160 62 1 <56 97 <56 62 0.3 <56 <56 <56 66 10 1100 2600 380 66 3 <74<120 <56 66 1 <56 <56 <56 66 0.3 <56 <56 <56 40 10 1600 1600 170 40 3990 1100 210 40 1 450 450 110 40 0.3 450 200 <29 44 10 1800 1600 790 443 1000 1500 <260 44 1 990 <260 <260 44 0.3 ˜570 510 <260 48 10 2000 2000˜540 48 3 1600 1600 ˜510 48 1 790 940 <260 48 0.3 <260 <260 <260 69 101000 1000 ≦340 69 3 ≦270 ≦150 <150 69 1 <150 <150 <150 69 0.3 <150 <150<150 85 10 2200 5700 ˜570 85 3 1500 4300 ˜430 85 1 ˜980 3900 ≦330 85 0.3670 670 <250 90 10 750 3500 ≦140 90 3 ≦130 570 ≦74 90 1 <74 <74 <74 900.3 <74 <74 <74 93 10 2100 2900 630 93 3 1300 1300 ˜260 93 1 660 1500340 93 0.3 400 360 ≦150 96 10 2900 4700 ˜350 96 3 3000 10000 960 96 13200 5000 1100 96 0.3 2900 3400 620 99 10 2500 4600 ˜220 99 3 1600 750˜220 99 1 2200 5100 460 99 0.3 1600 3500 390 104 10 3400 4500 ≦660 104 3≦660 2200 <380 104 1 ˜780 ˜780 ˜380 104 0.3 <380 <380 <380 115 10 56005300 870 115 3 2200 5300 ˜310 115 1 1400 2900 ˜310 115 0.3 ˜380 2500˜360 117 10 1100 480 ˜310 117 3 ˜820 2200 ˜310 117 1 ≦270 630 ≦270 1170.3 <160 1200 <160

[0215] These results show that the tested compounds induce interferonbiosynthesis at detectable levels in mice.

Induction of MC-26 Tumors in Mice

[0216] The test methods described below demonstrate the ability ofcompounds of the invention to inhibit tumor growth in mice.

[0217] On day 0 female CDF1 mice are inoculated i.v. with 4×10⁴ MC-26colon tumor cells in a volume of 0.2 ml of saline per mouse. The miceare sacrificed 14 days later. The lungs are removed and fixed with WARF(24% ethanol, 10% formalin, and 2% acetic acid in water) then allowed tostand for 30 minutes. The lobes are separated and the colonies arecounted. Five mice are in each treatment group and comparisons are madeto controls.

[0218] The mice in the treatment groups were dosed on days 3, 4, 5, 6,7, 10, 11, 12, 13, and 14, orally with a suspension of compound (30mg/kg) in water (10 mL/kg).

[0219] The mice in the control groups were dosed orally with saline (10mL/kg) on days 3, 4, 5, 6, and 7, and with water (10 mL/kg) on days 10,11, 12, 13, and 14.

[0220] Results are shown in the table below. Inhibition of MC-26 Tumorsin Mice Compound of Example Number of Colonies 11 204 ± 28 12 149 ± 2131 221 ± 37 34 196 ± 20 37 123 ± 31 Control 385 ± 31

[0221] On day 0 female CDF1 mice are inoculated i.v. with 1×10⁴ MC-26colon tumor cells in a volume of 0.2 mL of saline per mouse. The miceare sacrificed 21 days later. The lungs are removed and fixed with WARFthen allowed to stand for 30 minutes. The lobes are separated and thecolonies are counted. Ten mice are in each treatment group and in thecontrol group.

[0222] The mice in the control group were dosed orally with water (10mL/Kg) on days 0, 1, 2, 3 and 4. Four mice from this group died prior today 21.

[0223] The mice in the first treatment group were dosed on days 0, 1, 2,3 and 4 orally with a suspension of the compound of Example 99 (1 mg/Kg)in water (10 mL/Kg). One mouse from this group died prior to day 21.

[0224] The mice in the second treatment group were dosed on days 0, 1,2, 3 and 4 orally with a suspension of the compound of Example 99 (3mg/Kg) in water (10 mL/Kg). All of the mice in this treatment groupsurvived until day 21.

[0225] Results are shown in the table below. Inhibition of MC-26 Tumorsin Mice Treatment N Number of Colonies 3 mg/Kg 10 17 ± 3  1 mg/Kg 9 29 ±4  Control 6 55 ± 11

[0226] These results show that the tested compounds inhibit MC-26 tumorformation in mice.

Indirect In-Vitro Antiviral Activity

[0227] The test method described below demonstrates the ability ofcompounds of the invention to inhibit the progress of viral infection.

[0228] Whole blood is collected by venipuncture into EDTA vacutainertubes. Peripheral blood mononuclear cells (PBM) are isolated usingFicoll-Paque® solution (available from Pharmacia LKB Biotechnology Inc.,Piscataway, N.J.). The PBM are washed with phosphate buffer saline thendiluted with RPMI 1640 medium (available form GIBCO, Grand Island, N.Y.)to obtain a final concentration of 2.5×10⁶ cells/mL. One mL portions ofPBM in medium are placed in 15 mL polypropylene tubes. A 100 μL portionof autologous serum is added to each tube. The test compound isdissolved in dimethyl sulfoxide then diluted with RPMI 1640 medium. Thesolution of test compound is added to the tubes containing the PBM togive final concentrations ranging from 0.1 μg/mL to 10 μg/mL. Controltubes do not receive any test compound. The tubes are then incubated for24 hours at 37° C. with a 5% carbon dioxide atmosphere. Followingincubation the tubes are centrifuged at 400×g for 5 minutes. Thesupernatant is removed. The PBM's are brought up in 100 μL of RPMI 1640medium and then infected with a 100 μL containing 10⁵ tissue culture 50%infectious doses of vesicular stomatitis virus (VSV). The tubes areincubated for 30 minutes at 37° C. to allow virus adsorption. One mL ofRPMI 1640 medium is added to each tube and the tubes are incubated for48 hours at 37° C. The tubes are frozen then thawed to lyse the cells.The tubes are centrifuged at 400×g for 5 minutes to remove cellulardebris then the supernatant is assayed by serial tenfold dilutions onVero cells in 96 well microtiter plates. The infected cells areincubated for 24 hours at 37° C. before quantifying for viral cytopathiceffect. The viral cytopathic effect is quantified by staining with 0.05%crystal violet. Results are presented as VSV inhibition, defined as thelog₁₀ (control VSV yield/experimental VSV yield). Results are shown inthe table below wherein the absence of an entry indicates that thecompound was not tested at that particular dose concentration. Controltubes have a value of 0. In-vitro Antiviral Activity VSV YieldInhibition Dose Compound Concentration (μg/mL) of Example 10 5 1.0 0.50.1 15 5 5 6 — — 27 — — 4 3 4 31 6 5 5 — — 40 6 7 7 — — 44 — — 7 4 3 51— — 5 1 0 61 — — 5 7 5 66 — — 3 2 2 72 — — 5 5 5 77 — — 5 5 3 81 — — 5 45 85 — — 5 5 5 90 — — 5 4 5 93 — — 5 5 0 96 — — 5 5 6 99 — — 5 5 5

[0229] These results show that the tested compounds are active againstVSV.

What is claimed is:
 1. A compound of the formula:

wherein R₁ is selected from the group consisting of: hydrogen; straightchain or branched chain alkyl containing one to about ten carbon atomsand substituted straight chain or branched chain alkyl containing one toabout ten carbon atoms, wherein the substituent is selected from thegroup consisting of cycloalkyl containing three to about six carbonatoms and cycloalkyl containing three to about six carbon atomssubstituted by straight chain or branched chain alkyl containing one toabout four carbon atoms; straight chain or branched chain alkenylcontaining two to about ten carbon atoms and substituted straight chainor branched chain alkenyl containing two to about ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to about six carbon atoms and cycloalkylcontaining three to about six carbon atoms substituted by straight chainor branched chain alkyl containing one to about four carbon atoms;hydroxyalkyl of one to about six carbon atoms; alkoxyalkyl wherein thealkoxy moiety contains one to about four carbon atoms and the alkylmoiety contains one to about six carbon atoms; acyloxyalkyl wherein theacyloxy moiety is alkanoyloxy of two to about four carbon atoms orbenzoyloxy, and the alkyl moiety contains one to about six carbon atoms;benzyl; (phenyl)ethyl; and phenyl; said benzyl, (phenyl)ethyl or phenylsubstituent being optionally substituted on the benzene ring by one ortwo moieties independently selected from the group consisting of alkylof one to about four carbon atoms, alkoxy of one to about four carbonatoms, and halogen, with the proviso that when said benzene ring issubstituted by two of said moieties, then the moieties together containno more than six carbon atoms; R₂ and R₃ are independently selected fromthe group consisting of hydrogen, alkyl of one to about four carbonatoms, phenyl, and substituted phenyl wherein the substituent isselected from the group consisting of alkyl of one to about four carbonatoms, alkoxy of one to about four carbon atoms, and halogen; X isselected from the group consisting of alkoxy containing one to aboutfour carbon atoms, alkoxyalkyl wherein the alkoxy moiety contains one toabout four carbon atoms and the alkyl moiety contains one to about fourcarbon atoms, haloalkyl of one to about four carbon atoms, hydroxyalkylof one to about four carbon atoms, alkylamido wherein the alkyl groupcontains one to about four carbon atoms, amino, substituted aminowherein the substituent is alkyl or hydroxyalkyl of one to about fourcarbon atoms, azido, chloro, hydroxy, 1-morpholino, 1-pyrrolidino, andalkylthio of one to about four carbon atoms; and R is selected from thegroup consisting of hydrogen, straight chain or branched chain alkoxycontaining one to about four carbon atoms, halogen, and straight chainor branched chain alkyl containing one to about four carbon atoms; or apharmaceutically acceptable acid addition salt thereof.
 2. A compoundaccording to claim 1, wherein R₁ contains from two to about ten carbonatoms.
 3. A compound according to claim 1, wherein R₁ contains from twoto about eight carbon atoms.
 4. A compound according to claim 1, whereinR₁ is 2-hydroxy-2-methylpropyl or 2-methylpropyl.
 5. A compoundaccording to claim 1, wherein R₁ is benzyl.
 6. A compound according toclaim 1, wherein R₁ is alkoxyalkyl wherein the alkoxy moiety containsone to about four carbon atoms and the alkyl moiety contains two toabout six carbon atoms.
 7. A compound according to claim 6, wherein R₁is methoxyethyl or 3-methoxypropyl.
 8. A compound according to claim 1,wherein X is azido, ethoxy, hydroxy, methoxy, 1-morpholino, ormethylthio.
 9. A compound according to claim 1, wherein R is hydrogen.10. A compound according to claim 1, wherein R₂ is hydrogen and R₃ is4-chlorophenyl.
 11. A compound according to claim 1, wherein R₂ ishydrogen and R₃ is methyl.
 12. A compound according to claim 1, whereinR₂ and R₃ are methyl.
 13. A compound according to claim 1, wherein R₂and R₃ are hydrogen.
 14. A compound according to claim 1, wherein R₂ ishydrogen and R₃ is n-butyl.
 15. A compound according to claim 1, whereinR₂ is hydrogen and R₃ is phenyl.
 16. A compound according to claim 1,selected from the group consisting of:N-acetyl-4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methanamine;4-amino-7-chloro-_,_-dimethyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol4-amino-α-(4-chlorophenyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol;4-amino-_,_-dimethyl-2-hydroxymethyl-1H-imidazo-[4,5-c]quinoline-1-ethanol4-amino-_,_-dimethyl-2-methoxymethyl-1H-imidazo-[4,5-c]quinoline-1-ethanol4-amino-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol;4-amino-N-hydroxyethyl-N-methyl-1-phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methanaminehemihydrate;4-amino-_-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-ethanol4-amino-α-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methanol;4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol;4-amino-1-(2-methylpropyl)-α-phenyl-1H-imidazo[4,5-c]-quinoline-2-methanol;2-azidomethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine;2-chloromethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-aminehydrochloride;2-ethoxymethy-1-(3-methoxypropyl)-1H-imidazo[4,5-c]-quinolin-4-amine;2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine;2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinolin-4-amine2-(α-methoxybenzyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine;1-(2-methoxyethyl)-2-methoxymethyl-1H-imidazo[4,5-c]-quinolin-4-amine;2-(2-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinolin-4-amine2-(1-methoxyethyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine;2-methoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinolin-4-amine;2-methoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinolin-4-amine2-(1-methoxypentyl)-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.2-(2-methoxypropyl)-1-(2-methylpropyl)-1H-imidazo-[4,5-c]-4-amine1-(2-methylpropyl)-2-morpholinomethyl-1H-imidazo[4,5-c]quinolin-4-amine;1-(2-methylpropyl)-2-pyrrolidinomethyl-1H-imidazo-[4,5-c]quinolin-4-amine;2-methylthiomethyl-1-phenylmethyl-1H-imidazo [4,5-c]-quinolin-4-amine;2-morpholinomethyl-1-phenylmethyl-1H-imidazo[4,5-c]-quinolin-4-amine;and2-[1-(1-morpholino)pentyl]-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.17. A compound according to claim 1, selected from the group consistingof:4-amino-α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]-quinoline-2-methanol;4-amino-_,_-dimethyl-2-ethoxymethyl-1H-imidazo-[4,5-c]quinoline-1-ethanol;and 4-amino-1-phenylmethyl-1H-imidazo[4,5-c]quinoline-2-methanol.
 18. Acompound of the formula:

wherein R₅ is selected from the group consisting of: straight chain orbranched chain alkyl containing one to about ten carbon atoms andsubstituted straight chain or branched chain alkyl containing one toabout ten carbon atoms, wherein the substituent is selected from thegroup consisting of cycloalkyl containing three to about six carbonatoms and cycloalkyl containing three to about six carbon atomssubstituted by straight chain or branched chain alkyl containing one toabout four carbon atoms; straight chain or branched chain alkenylcontaining two to about ten carbon atoms and substituted straight chainor branched chain alkenyl containing two to about ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to about six carbon atoms and cycloalkylcontaining three to about six carbon atoms substituted by straight chainor branched chain alkyl containing one to about four carbon atoms;alkoxyalkyl wherein the alkoxy moiety contains one to about four carbonatoms and the alkyl moiety contains one to about six carbon atoms;acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to aboutfour carbon atoms or benzoyloxy, and the alkyl moiety contains one toabout six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl,(phenyl)ethyl or phenyl substituent being optionally substituted on thebenzene ring by one or two moieties independently selected from thegroup consisting of alkyl of one to about four carbon atoms, alkoxy ofone to about four carbon atoms, and halogen, with the proviso that whensaid benzene ring is substituted by two of said moieties, then themoieties together contain no more than six carbon atoms; R₂ and R₃ areindependently selected from the group consisting of hydrogen, alkyl ofone to about four carbon atoms, phenyl, and substituted phenyl whereinthe substituent is selected from the group consisting of alkyl of one toabout four carbon atoms, alkoxy of one to about four carbon atoms, andhalogen; P is selected from the group consisting of alkanolyloxy,alkanoyloxyalkyl wherein the alkyl moiety contains one to about fourcarbon atoms, and aroyloxy; and R is selected from the group consistingof hydrogen, straight chain or branched chain alkoxy containing one toabout four carbon atoms, halogen, and straight chain or branched chainalkyl containing one to about four carbon atoms.
 19. A compoundaccording to claim 18, wherein R₅ contains from two to about ten carbonatoms.
 20. A compound according to claim 18, wherein R₅ contains fromtwo to about eight carbon atoms.
 21. A compound according to claim 18,wherein R₅ is 2-methylpropyl.
 22. A compound according to claim 18,wherein R₅ is benzyl.
 23. A compound according to claim 18, wherein R₅is alkoxyalkyl wherein the alkoxy moiety contains one to about fourcarbon atoms and the alkyl moiety contains one to about six carbonatoms.
 24. A compound according to claim 18, wherein Rs is methoxyethylor 3-methoxypropyl.
 25. A compound according to claim 18, wherein P isacetoxy or benzoyloxy.
 26. A compound according to claim 18, wherein Ris hydrogen.
 27. A compound according to claim 18, wherein R₂ ishydrogen and R₃ is 4-chlorophenyl.
 28. A compound according to claim 18,wherein R₂ is hydrogen and R₃ is methyl.
 29. A compound according toclaim 18, wherein R₂ and R₃ are methyl.
 30. A compound according toclaim 18, wherein R₂ and R₃ are hydrogen.
 31. A compound according toclaim 18, wherein R₂ is hydrogen and R₃ is n-butyl.
 32. A compoundaccording to claim 18, wherein R₂ is hydrogen and R₃ is phenyl.
 33. Acompound according to claim 18, selected from the group consisting of4-amino-_-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methylacetate and4-amino-_-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-ethylacetate.
 34. A compound of the formula

wherein Y is —NO₂ or —NH₂; R₄ is alkoxyalkyl wherein the alkoxy moietycontains one to about four carbon atoms and the alkyl moiety containstwo to about six carbon atoms; and R is selected from the groupconsisting of hydrogen, straight chain or branched chain alkoxycontaining one to about four carbon atoms, halogen, and straight chainor branched chain alkyl containing one to about four carbon atoms.
 35. Acompound according to claim 34, wherein R₄ is methoxyethyl or3-methoxypropyl.
 36. A compound of the formula

wherein R₄′ is alkoxyalkyl wherein the alkoxy moiety contains one toabout four carbon atoms and the alkyl moiety contains one to about sixcarbon atoms; and R is selected from the group consisting of hydrogen,straight chain or branched chain alkoxy containing one to about fourcarbon atoms, halogen, and straight chain or branched chain alkylcontaining one to about four carbon atoms.
 37. A compound according toclaim 36, wherein R₄ is methoxyethyl or 3-methoxypropyl.
 38. A compoundaccording to claim 36, wherein R is hydrogen.
 39. A compound of theformula

wherein R₅ is selected from the group consisting of: straight chain orbranched chain alkyl containing one to about ten carbon atoms andsubstituted straight chain or branched chain alkyl containing one toabout ten carbon atoms, wherein the substituent is selected from thegroup consisting of cycloalkyl containing three to about six carbonatoms and cycloalkyl containing three to about six carbon atomssubstituted by straight chain or branched chain alkyl containing one toabout four carbon atoms; straight chain or branched chain alkenylcontaining two to about ten carbon atoms and substituted straight chainor branched chain alkenyl containing two to about ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to about six carbon atoms and cycloalkylcontaining three to about six carbon atoms substituted by straight chainor branched chain alkyl containing one to about four carbon atoms;alkoxyalkyl wherein the alkoxy moiety contains one to about four carbonatoms and the alkyl moiety contains one to about six carbon atoms;acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to aboutfour carbon atoms or benzoyloxy, and the alkyl moiety contains one toabout six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl,(phenyl)ethyl, or phenyl substituent being optionally substituted on thebenzene ring by one or two moieties independently selected from thegroup consisting of alkyl of one to about four carbon atoms, alkoxy ofone to about four carbon atoms, and halogen, with the proviso that whensaid benzene ring is substituted by two of said moieties, then themoieties together contain no more than six carbon atoms; R₂ and R₃ areindependently selected from the group consisting of hydrogen, alkyl ofone to about four carbon atoms, phenyl, and substituted phenyl whereinthe substituent is selected from the group consisting of alkyl of one toabout four carbon atoms, alkoxy of one to about four carbon atoms, andhalogen; G is selected from the group consisting of alkoxy containingone to about four carbon atoms, alkoxyalkyl wherein the alkoxy moietycontains one to about four carbon atoms and the alkyl moiety containsone to about four carbon atoms, alkylamido wherein the alkyl groupcontains one to about four carbon atoms, azido, chloro, 1-morpholino,1-pyrrolidino, alkylthio of one to about four carbon atoms, alkanoyloxy,alkanoyloxyalkyl wherein the alkyl moiety contains one to about fourcarbon atoms, and aroyloxy, with the proviso that when G is alkylamidothen R₅ is alkenyl, substituted alkenyl, or alkoxyalkyl; and R isselected from the group consisting of hydrogen, straight chain orbranched chain alkoxy containing one to about four carbon atoms,halogen, and straight chain or branched chain alkyl containing one toabout four carbon atoms.
 40. A compound of the formula

wherein R₅ is selected from the group consisting of: straight chain orbranched chain alkyl containing one to about ten carbon atoms andsubstituted straight chain or branched chain alkyl containing one toabout ten carbon atoms, wherein the substituent is selected from thegroup consisting of cycloalkyl containing three to about six carbonatoms and cycloalkyl containing three to about six carbon atomssubstituted by straight chain or branched chain alkyl containing one toabout four carbon atoms; straight chain or branched chain alkenylcontaining two to about ten carbon atoms and substituted straight chainor branched chain alkenyl containing two to about ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to about six carbon atoms and cycloalkylcontaining three to about six carbon atoms substituted by straight chainor branched chain alkyl containing one to about four carbon atoms;alkoxyalkyl wherein the alkoxy moiety contains one to about four carbonatoms and the alkyl moiety contains one to about six carbon atoms;acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy of two to aboutfour carbon atoms or benzoyloxy, and the alkyl moiety contains one toabout six carbon atoms; benzyl; (phenyl)ethyl; and phenyl; said benzyl,(phenyl)ethyl, or phenyl substituent being optionally substituted on thebenzene ring by one or two moieties independently selected from thegroup consisting of alkyl of one to about four carbon atoms, alkoxy ofone to about four carbon atoms, and halogen, with the proviso that whensaid benzene ring is substituted by two of said moieties, then themoieties together contain no more than six carbon atoms; R₂ and R₃ areindependently selected from the group consisting of hydrogen, alkyl ofone to about four carbon atoms, phenyl, and substituted phenyl whereinthe substituent is selected from the group consisting of alkyl of one toabout four carbon atoms, alkoxy of one to about four carbon atoms, andhalogen; Z is selected from the group consisting of alkoxy containingone to about four carbon atoms, alkoxyalkyl wherein the alkoxy moietycontains one to about four carbon atoms and the alkyl moiety containsone to about four carbon atoms, hydroxyalkyl containing one to aboutfour carbon atoms, oxoalkyl of two to about four carbon atoms,alkanoyloxyalkyl wherein the alkyl moiety contains one to about fourcarbon atoms, alkylamido wherein the alkyl group contains one to aboutfour carbon atoms, substituted amino wherein the substituent is alkyl orhydroxyalkyl of one to about four carbon atoms, azido, chloro,1-morpholino, 1-pyrrolidino, alkylthio of one to about four carbonatoms, hydroxy, alkanoyloxy, and aroyloxy; Q is selected from the groupconsisting of hydrogen, chloro, and R_(i)-E-NH— wherein R_(i) is anorganic group substantially inert to quinoline N-oxides and E is ahydrolytically active functional group; with the proviso that when Q isR_(i)-E-NH, then Z is other than hydroxy, substituted amino, orhydroxyalkyl as defined above, and with the further proviso that when Qis hydrogen or chloro and Z is alkylamido or hydroxyalkyl, then R₅ isalkenyl, substituted alkenyl, or alkoxyalkyl; and R is selected from thegroup consisting of hydrogen, straight chain or branched chain alkoxycontaining one to about four carbon atoms, halogen, and straight chainor branched chain alkyl containing one to about four carbon atoms. 41.An antiviral pharmaceutical composition comprising a compound accordingto claim 1 and a pharmaceutically acceptable vehicle, the compound beingpresent in an amount effective to inhibit and/or prevent the progress ofa viral infection.
 42. A method of treating a mammal infected with avirus, comprising administering to the mammal a compound according toclaim 1 in an amount effective to inhibit and/or prevent the infection.43. A method according to claim 42, wherein the virus is Type II Herpessimplex.
 44. A method of inducing interferon biosynthesis in a mammal,which method comprises administering to the mammal a compound accordingto claim 1 in an amount sufficient to induce interferon biosynthesis.45. A method of inhibiting the growth of a tumor in a mammal, whichmethod comprises administering to the mammal a compound according toclaim 1 in an amount sufficient to inhibit the growth of said tumor. 46.A compound according to claim 1, wherein R₁ is selected from the groupconsisting of: hydrogen; straight chain or branched chain alkylcontaining one to about ten carbon atoms and substituted straight chainor branched chain alkyl containing one to about ten carbon atoms,wherein the substituent is selected from the group consisting ofcycloalkyl containing three to about six carbon atoms and cycloalkylcontaining three to about six carbon atoms substituted by straight chainor branched chain alkyl containing one to about four carbon atoms;straight chain or branched chain alkenyl containing two to about tencarbon atoms and substituted straight chain or branched chain alkenylcontaining two to about ten carbon atoms, wherein the substituent isselected from the group consisting of cycloalkyl containing three toabout six carbon atoms and cycloalkyl containing three to about sixcarbon atoms substituted by straight chain or branched chain alkylcontaining one to about four carbon atoms; hydroxyalkyl of one to aboutsix carbon atoms; alkoxyalkyl wherein the alkoxy moiety contains one toabout four carbon atoms and the alkyl moiety contains one to about sixcarbon atoms; acyloxyalkyl wherein the acyloxy moiety is alkanoyloxy oftwo to about four carbon atoms or benzoyloxy, and the alkyl moietycontains one to about six carbon atoms; benzyl; (phenyl)ethyl; andphenyl; said benzyl, (phenyl)ethyl or phenyl substituent beingoptionally substituted on the benzene ring by one or two moietiesindependently selected from the group consisting of alkyl of one toabout four carbon atoms, alkoxy of one to about four carbon atoms, andhalogen, with the proviso that when said benzene ring is substituted bytwo of said moieties, then the moieties together contain no more thansix carbon atoms; R₂ and R₃ are independently selected from the groupconsisting of hydrogen, alkyl of one to about four carbon atoms, phenyl,and substituted phenyl wherein the substituent is selected from thegroup consisting of alkyl of one to about four carbon atoms, alkoxy ofone to about four carbon atoms, and halogen; X is selected from thegroup consisting of alkoxy containing one to about four carbon atoms,alkylamido wherein the alkyl group contains one to about four carbonatoms, amino, substituted amino wherein the substituent is alkyl orhydroxyalkyl of one to about four carbon atoms, azido, chloro, hydroxy,1-morpholino, 1-pyrrolidino, and alkylthio of one to about four carbonatoms; and R is selected from the group consisting of hydrogen, straightchain or branched chain alkoxy containing one to about four carbonatoms, halogen, and straight chain or branched chain alkyl containingone to about four carbon atoms; or a pharmaceutically acceptable acidaddition salt thereof.
 47. A compound according to claim 1, selectedfrom the group consisting of2-ethoxymethyl-1-(3-methylbutyl)-1H-imidazo[4,5-c]quinolin-4-amine,4-amino-α,α-dimethyl-2-methoxymethyl-1H-imidazo[4,5-c]quinoline-1-ethanol,1-butyl-2-methoxyethyl-1H-imidazo[4,5-c]quinolin-4-amine,1-butyl-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine,4-amino-2-ethoxymethyl-α-ethyl-α-methyl-1H-imidazo[4,5-c]quinoline-1-ethanol,and 4-amino-1-butyl-1H-imidazo[4,5-c]quinoline-2-methanol, or apharmaceutically acceptable acid addition salt thereof.